SOX9 is a SOXE-family transcription factor that plays dual core roles in development. First, SOX9 is the master regulator of chondrogenesis, cooperating with SOX5 and SOX6 to drive cartilage matrix gene expression (COL2A1, ACAN) and promoting chondrocyte differentiation while antagonizing osteoblast differentiation via beta-catenin inhibition. Second, SOX9 is critical for oligodendrocyte differentiation and glial fate specification, promoting glial over neuronal fates in the CNS. SOX9 binds AACAAT-centered DNA motifs via its HMG-box domain, bends DNA, and recruits co-activators CBP/p300 and TIP60. It functions exclusively in the nucleus with nuclear localization and export signals. Post-translational modifications including phosphorylation, acetylation, and sumoylation regulate its activity. While SOX9 has additional developmental roles in sex determination, heart valve, kidney, and other epithelial programs, its core molecular functions center on transcriptional activation in cartilage and glial lineages.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0000981
DNA-binding transcription factor activity, RNA polymerase II-specific
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: SOX9 is a bona fide RNA Pol II transcription factor with experimentally validated
DNA-binding and transactivation domains (deep research, UniProt). It binds the
AACAAT motif via HMG-box and activates transcription of cartilage and other target
genes.
Reason: This is a core molecular function of SOX9. The IBA annotation correctly captures
SOX9's role as an RNA Pol II-specific transcription factor, supported by extensive
experimental evidence showing DNA binding, transactivation, and regulation of Pol
II-transcribed genes.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
SOX9 is a human SOXE-family transcription factor essential for lineage specification... binds AACAAT-centered motifs via its HMG-box... recruits co-activators CBP/p300 and TIP60
file:human/SOX9/SOX9-deep-research-falcon.md
model: Edison Scientific Literature
|
|
GO:0002009
morphogenesis of an epithelium
|
IBA
GO_REF:0000033 |
KEEP AS NON CORE |
Summary: SOX9 regulates epithelial morphogenesis in multiple organs including lung, kidney,
intestine, and prostate. Deep research notes roles in lung epithelium during
branching morphogenesis and kidney epithelial branching.
Reason: While well-supported, epithelial morphogenesis represents peripheral developmental
processes rather than the core chondrogenic and gliogenic transcription factor
functions of SOX9. This is a pleiotropic effect.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
involved in the lung epithelium during branching morphogenesis... Controls epithelial branching during kidney development
|
|
GO:0005634
nucleus
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: SOX9 functions in the nucleus with validated nuclear localization signals and
nuclear export signals. UniProt describes nuclear localization, and deep research
confirms nuclear function.
Reason: Nuclear localization is essential for SOX9's transcription factor function. Multiple
lines of evidence support this including NLS/NES identification and experimental
demonstration of nuclear localization.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
SOX9 harbors nuclear localization and export signals... SOX9 functions in the nucleus
file:human/SOX9/SOX9-uniprot.txt
SUBCELLULAR LOCATION: Nucleus
|
|
GO:0007507
heart development
|
IBA
GO_REF:0000033 |
KEEP AS NON CORE |
Summary: SOX9 is involved in heart valve development and aortic valve morphogenesis with
IDA evidence (PMID:22110751). GOA file shows multiple heart-related annotations.
Reason: Heart development is a legitimate but peripheral function of SOX9. The core
functions are chondrogenesis and gliogenesis. Heart valve development is a
pleiotropic effect.
Supporting Evidence:
file:human/SOX9/SOX9-goa.tsv
GO:0003180 aortic valve morphogenesis biological_process ECO:0000314 IDA PMID:22110751
|
|
GO:0000122
negative regulation of transcription by RNA polymerase II
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: SOX9 can act as both activator and repressor. IMP evidence (PMID:24014021,
PMID:29503843) shows SOX9 can negatively regulate transcription. Deep research
notes SOX9 antagonizes beta-catenin.
Reason: SOX9 has documented repressive functions including inhibition of osteoblast genes
and antagonism of beta-catenin signaling. This is part of its core regulatory
mechanism in maintaining chondrocyte identity.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
Antagonizes β-catenin in chondrocytes... prevents osteoblastic differentiation of chondrocytes by lowering beta-catenin (CTNNB1) signaling
file:human/SOX9/SOX9-goa.tsv
GO:0000122 negative regulation of transcription by RNA polymerase II biological_process ECO:0000314 IDA PMID:29503843
|
|
GO:0000978
RNA polymerase II cis-regulatory region sequence-specific DNA binding
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: SOX9 binds to enhancer and promoter regions with sequence specificity. Deep
research describes binding to AACAAT-centered motifs in enhancers and super-enhancers.
Reason: This is a core molecular function. SOX9 recognizes specific DNA sequences via its
HMG-box domain and binds to cis-regulatory regions to activate transcription.
Well-supported by experimental evidence.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
Specifically binds the 5'-ACAAAG-3' DNA motif present in enhancers and super-enhancers
file:human/SOX9/SOX9-goa.tsv
GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding molecular_function ECO:0000314 IDA PMID:22110751
|
|
GO:0002062
chondrocyte differentiation
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: SOX9 is the master regulator of chondrocyte differentiation. Deep research and
UniProt extensively document this role with multiple IDA/IMP evidence codes.
Reason: This is arguably THE core biological process for SOX9. It is absolutely required
for chondrogenesis and is the most well-characterized function of SOX9. Extensively
validated experimentally.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
SOX9 is a human SOXE-family transcription factor essential for lineage specification... orchestrate chondrogenesis
file:human/SOX9/SOX9-uniprot.txt
Transcription factor that plays a key role in chondrocytes differentiation and skeletal development
|
|
GO:0032332
positive regulation of chondrocyte differentiation
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: SOX9 promotes chondrocyte differentiation with multiple IDA/IMP evidence codes
(PMID:21401405, PMID:20676705). This is a more specific term capturing SOX9's
role as a positive regulator.
Reason: This is core function. SOX9 positively drives chondrocyte differentiation through
direct transcriptional activation of cartilage genes and is required for multiple
stages of chondrogenesis.
Supporting Evidence:
file:human/SOX9/SOX9-goa.tsv
GO:0032332 positive regulation of chondrocyte differentiation biological_process ECO:0000314 IDA PMID:21401405
|
|
GO:0048709
oligodendrocyte differentiation
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: SOX9 promotes oligodendrocyte differentiation and glial fate specification. This
is a critical function in neural development where SOX9 promotes glial over
neuronal fates.
Reason: This is a CORE function for the NEURON_DEVELOPMENT project context. SOX9 is
essential for oligodendrocyte lineage specification and is the glial counterpart
to proneural factors. This is NOT a peripheral function but rather one of SOX9's
two major core roles (cartilage AND glia).
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
GLIOGENESIS/OLIGODENDROCYTE DIFFERENTIATION - important for glial fate specification
|
|
GO:0003677
DNA binding
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: SOX9 binds DNA via its HMG-box domain. This is a well-established molecular
function but is somewhat generic compared to the sequence-specific binding terms.
Reason: DNA binding is a fundamental molecular function of SOX9. While more specific terms
exist (sequence-specific binding), this parent term is also accurate and appropriate.
Supporting Evidence:
file:human/SOX9/SOX9-uniprot.txt
DNA_BIND 105..173 /note='HMG box'
|
|
GO:0005634
nucleus
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Duplicate of earlier nucleus annotation. Same evidence and conclusion.
Reason: Duplicate annotation with IEA evidence. Nuclear localization is well-established.
Supporting Evidence:
file:human/SOX9/SOX9-uniprot.txt
SUBCELLULAR LOCATION: Nucleus
|
|
GO:0030154
cell differentiation
|
IEA
GO_REF:0000043 |
ACCEPT |
Summary: SOX9 is involved in differentiation of multiple cell types including chondrocytes,
glia, Sertoli cells, and various epithelial cells. This is a very broad parent term.
Reason: While generic, this term is accurate. SOX9 drives differentiation programs in
multiple lineages. More specific child terms are preferred but this parent term
is not incorrect.
Supporting Evidence:
file:human/SOX9/SOX9-uniprot.txt
Also acts as a regulator of proliferation and differentiation in epithelial stem/progenitor cells
|
|
GO:0045893
positive regulation of DNA-templated transcription
|
IEA
GO_REF:0000117 |
ACCEPT |
Summary: SOX9 activates transcription as documented extensively. This is a parent term
less specific than the RNA Pol II terms but still accurate.
Reason: This broad term accurately captures SOX9's transactivation function. More specific
RNA Pol II terms are preferred but this is not incorrect.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
recruits co-activators CBP/p300 and TIP60... promotes expression of genes important for chondrogenesis
|
|
GO:1990837
sequence-specific double-stranded DNA binding
|
IEA
GO_REF:0000117 |
ACCEPT |
Summary: SOX9 binds double-stranded DNA at specific sequences via its HMG-box domain.
IDA evidence exists (PMID:28473536).
Reason: This accurately describes SOX9's DNA-binding mode. The HMG-box recognizes specific
sequences in double-stranded DNA and bends it.
Supporting Evidence:
file:human/SOX9/SOX9-goa.tsv
GO:1990837 sequence-specific double-stranded DNA binding molecular_function ECO:0000314 IDA PMID:28473536
|
|
GO:0005515
protein binding
|
IPI
PMID:12810722 A SOX9 defect of calmodulin-dependent nuclear import in camp... |
REMOVE |
Summary: Generic protein binding term from IPI evidence. SOX9 interacts with many partners
including SOX5/6, CBP/p300, beta-catenin, but this term lacks specificity.
Reason: Per guidelines, avoid generic "protein binding" annotations as they don't convey
informative molecular function. More specific binding terms (e.g., transcription
co-activator binding) would be better if available.
Supporting Evidence:
PMID:12810722
2003 Jun 16. A SOX9 defect of calmodulin-dependent nuclear import in campomelic dysplasia/autosomal sex reversal.
|
|
GO:0005515
protein binding
|
IPI
PMID:21346191 Arid5a cooperates with Sox9 to stimulate chondrocyte-specifi... |
REMOVE |
Summary: Duplicate generic protein binding annotation from different reference.
Reason: Same rationale as previous protein binding annotation. Generic and uninformative
for molecular function.
Supporting Evidence:
PMID:21346191
2011 Feb 23. Arid5a cooperates with Sox9 to stimulate chondrocyte-specific transcription.
|
|
GO:0000976
transcription cis-regulatory region binding
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: SOX9 binds to enhancers and promoters. This is a parent term to the more specific
RNA Pol II cis-regulatory region binding.
Reason: Accurate term capturing SOX9's binding to regulatory regions. More specific child
terms exist but this is appropriate.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
binds the DNA minor groove... engages enhancer architectures
|
|
GO:0000978
RNA polymerase II cis-regulatory region sequence-specific DNA binding
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: Duplicate of earlier IBA annotation for same term. Same evidence supports.
Reason: Duplicate but accurate annotation of core molecular function.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
Specifically binds the 5'-ACAAAG-3' DNA motif present in enhancers and super-enhancers
|
|
GO:0000981
DNA-binding transcription factor activity, RNA polymerase II-specific
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: Duplicate of first IBA annotation. Multiple evidence codes support.
Reason: Core molecular function, well-supported.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
SOX9 is a human SOXE-family transcription factor
|
|
GO:0000987
cis-regulatory region sequence-specific DNA binding
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Another term for sequence-specific binding to regulatory regions. Slight variation
in term hierarchy from GO:0000978.
Reason: Accurate molecular function term. While overlapping with other DNA-binding terms,
this captures the regulatory region specificity.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
binds AACAAT-centered motifs via its HMG-box
|
|
GO:0001228
DNA-binding transcription activator activity, RNA polymerase II-specific
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: SOX9 has transcriptional activator activity with documented transactivation
domains (TAM and TAC). Multiple IDA evidence codes exist.
Reason: Core molecular function. SOX9 is primarily a transcriptional activator, though
it can also repress. Activator function is well-documented.
Supporting Evidence:
file:human/SOX9/SOX9-uniprot.txt
The transactivation domains TAM and TAC (for transactivation domain in the middle and at the C-terminus, respectively)
file:human/SOX9/SOX9-goa.tsv
GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific molecular_function ECO:0000314 IDA PMID:21367821
|
|
GO:0001503
ossification
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: SOX9 is involved in skeletal development and endochondral ossification, where it
regulates the cartilage template that is replaced by bone.
Reason: While SOX9 affects ossification (primarily by regulating the cartilage template
for endochondral bone formation), this is a consequence of its chondrogenic
function rather than a distinct core role. The core function is chondrogenesis.
Supporting Evidence:
file:human/SOX9/SOX9-uniprot.txt
maintains chondrocyte columnar proliferation, delays prehypertrophy and then prevents osteoblastic differentiation
|
|
GO:0001658
branching involved in ureteric bud morphogenesis
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: SOX9 regulates kidney development including ureteric bud branching.
Reason: Kidney development is a peripheral developmental role, not part of the core
cartilage/glial functions. Pleiotropic effect.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
Controls epithelial branching during kidney development
|
|
GO:0001894
tissue homeostasis
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: SOX9 plays roles in maintaining tissue homeostasis in intestinal epithelium and
other tissues.
Reason: Tissue homeostasis represents peripheral maintenance functions rather than core
transcription factor activities in cartilage and glial development.
Supporting Evidence:
file:human/SOX9/SOX9-goa.tsv
GO:0060729 intestinal epithelial structure maintenance biological_process
|
|
GO:0002062
chondrocyte differentiation
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: Duplicate of earlier IBA annotation for chondrocyte differentiation.
Reason: Core function, multiple evidence codes support.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
master regulator of chondrocyte differentiation
|
|
GO:0002683
negative regulation of immune system process
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: SOX9 may have immunomodulatory effects in certain contexts, but this is not
well-documented as a primary function.
Reason: Immune regulation is a peripheral effect, not related to core chondrogenic or
gliogenic functions. Likely context-dependent pleiotropic effect.
|
|
GO:0003170
heart valve development
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: SOX9 is involved in heart valve development with experimental evidence.
Reason: Heart valve development is peripheral to core functions.
Supporting Evidence:
file:human/SOX9/SOX9-goa.tsv
GO:0003180 aortic valve morphogenesis biological_process ECO:0000314 IDA PMID:22110751
|
|
GO:0003415
chondrocyte hypertrophy
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: SOX9 regulates chondrocyte hypertrophy. UniProt notes SOX9 is required for
chondrocyte hypertrophy both indirectly and directly.
Reason: Chondrocyte hypertrophy is part of SOX9's core chondrogenic program. This is a
specific stage of chondrocyte maturation that SOX9 controls.
Supporting Evidence:
file:human/SOX9/SOX9-uniprot.txt
Also required for chondrocyte hypertrophy, both indirectly, by keeping the lineage fate of chondrocytes, and directly, by remaining present in upper hypertrophic cells
|
|
GO:0003430
growth plate cartilage chondrocyte growth
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: SOX9 maintains chondrocyte proliferation in growth plate cartilage as part of
its chondrogenic program.
Reason: Growth plate chondrocyte regulation is part of SOX9's core chondrogenic function.
This represents a specific developmental stage in cartilage biology.
Supporting Evidence:
file:human/SOX9/SOX9-uniprot.txt
maintains chondrocyte columnar proliferation
|
|
GO:0003700
DNA-binding transcription factor activity
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: General parent term for transcription factor activity. Less specific than RNA
Pol II-specific terms.
Reason: Accurate but broad molecular function term. More specific child terms are preferred
but this is not incorrect.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
SOX9 is a human SOXE-family transcription factor
|
|
GO:0005667
transcription regulator complex
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: SOX9 forms complexes with partner proteins including SOX5/6, CBP/p300. It can
also homodimerize.
Reason: SOX9 functions as part of transcriptional regulatory complexes, cooperating with
SOX5/6 on paired SOX sites and recruiting coactivators. This is accurate.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
frequently in cooperation with SOX5/6 on paired SOX sites
file:human/SOX9/SOX9-uniprot.txt
Homodimer; homodimerization is required for activity
|
|
GO:0007165
signal transduction
|
IEA
GO_REF:0000107 |
MARK AS OVER ANNOTATED |
Summary: Extremely broad term. SOX9 responds to and mediates signaling pathways like BMP,
TGF-beta, but this term is too generic.
Reason: This term is overly broad and uninformative. SOX9 participates in specific
signaling contexts but "signal transduction" as a general term doesn't capture
its function meaningfully.
|
|
GO:0007173
epidermal growth factor receptor signaling pathway
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: SOX9 is involved in EGFR signaling in urothelial and other epithelial contexts.
Deep research mentions EGFR-ERK-SOX9 cascade.
Reason: EGFR pathway involvement is context-specific (urothelium, epithelial regeneration)
and peripheral to core functions. Not part of cartilage/glial programs.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
An EGFR-ERK-SOX9 signaling cascade links urothelial development and regeneration to cancer
|
|
GO:0007417
central nervous system development
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: SOX9 promotes glial fate specification and oligodendrocyte differentiation in
the CNS. This is one of its core functions.
Reason: CNS development via gliogenesis is a CORE function of SOX9 in the NEURON_DEVELOPMENT
project context. SOX9 promotes glial over neuronal fates.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
GLIOGENESIS/OLIGODENDROCYTE DIFFERENTIATION - important for glial fate specification
|
|
GO:0008013
beta-catenin binding
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: SOX9 interacts with beta-catenin to antagonize Wnt signaling in chondrocytes.
This is a specific and informative binding term.
Reason: Beta-catenin binding is a specific molecular function relevant to SOX9's mechanism
of action. Unlike generic "protein binding," this term conveys functional information
about SOX9's antagonism of Wnt signaling.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
Antagonizes β-catenin in chondrocytes
file:human/SOX9/SOX9-uniprot.txt
Interacts with beta-catenin (CTNNB1); inhibiting CTNNB1 activity by competing with the binding sites of TCF/LEF within CTNNB1
|
|
GO:0010467
gene expression
|
IEA
GO_REF:0000107 |
MARK AS OVER ANNOTATED |
Summary: Extremely generic term for any gene expression regulation.
Reason: Too broad to be informative. More specific terms about transcriptional regulation
better capture SOX9's function.
|
|
GO:0010628
positive regulation of gene expression
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: Slightly more specific than gene expression but still quite broad. Has IDA
evidence (PMID:24681825).
Reason: While broad, this accurately captures SOX9's role as a transcriptional activator.
More specific terms are preferred but this is acceptable.
Supporting Evidence:
file:human/SOX9/SOX9-goa.tsv
GO:0010628 positive regulation of gene expression biological_process ECO:0000314 IDA PMID:24681825
|
|
GO:0030279
negative regulation of ossification
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: SOX9 delays ossification by maintaining cartilage and preventing premature
osteoblast differentiation. Has IDA evidence (PMID:29503843).
Reason: This is part of SOX9's core chondrogenic program. SOX9 blocks osteoblast
differentiation to maintain chondrocyte identity, which delays ossification.
Supporting Evidence:
file:human/SOX9/SOX9-uniprot.txt
prevents osteoblastic differentiation of chondrocytes by lowering beta-catenin (CTNNB1) signaling
file:human/SOX9/SOX9-goa.tsv
GO:0030279 negative regulation of ossification biological_process ECO:0000314 IDA PMID:29503843
|
|
GO:0030850
prostate gland development
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: SOX9 is expressed in prostate development with IEP evidence.
Reason: Prostate development is a peripheral epithelial developmental role, not core
cartilage/glial function.
Supporting Evidence:
file:human/SOX9/SOX9-goa.tsv
GO:0030850 prostate gland development biological_process ECO:0000270 IEP PMID:20103652
|
|
GO:0030879
mammary gland development
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: SOX9 plays roles in mammary gland epithelial development.
Reason: Peripheral epithelial developmental function.
|
|
GO:0030903
notochord development
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: SOX9 is involved in notochord development.
Reason: Notochord development is a developmental process but peripheral to core cartilage/glial
functions.
|
|
GO:0032332
positive regulation of chondrocyte differentiation
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: Duplicate of earlier IBA annotation for same term.
Reason: Core function with multiple evidence codes.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
master regulator of chondrocyte differentiation
|
|
GO:0043425
bHLH transcription factor binding
|
IEA
GO_REF:0000107 |
UNDECIDED |
Summary: SOX9 may interact with bHLH transcription factors in certain contexts, but this
is not well-documented as a major interaction.
Reason: Unclear if this represents a significant molecular function for SOX9. Would need
to review evidence for specific bHLH factor interactions relevant to SOX9's core
functions.
|
|
GO:0043565
sequence-specific DNA binding
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: SOX9 binds DNA in sequence-specific manner via AACAAT motif recognition. Has
IDA evidence (PMID:31194875).
Reason: Core molecular function, well-supported.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
binds AACAAT-centered motifs via its HMG-box
file:human/SOX9/SOX9-goa.tsv
GO:0043565 sequence-specific DNA binding molecular_function ECO:0000314 IDA PMID:31194875
|
|
GO:0045668
negative regulation of osteoblast differentiation
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: SOX9 blocks osteoblast differentiation to maintain chondrocyte identity. Has
ISS evidence.
Reason: This is part of SOX9's core mechanism for maintaining chondrocyte fate. SOX9
antagonizes osteoblast genes and beta-catenin to prevent osteogenesis.
Supporting Evidence:
file:human/SOX9/SOX9-uniprot.txt
prevents osteoblastic differentiation of chondrocytes
|
|
GO:0045944
positive regulation of transcription by RNA polymerase II
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: SOX9 activates RNA Pol II transcription with multiple IDA/IMP evidence codes.
Reason: Core transcriptional activator function, well-supported.
Supporting Evidence:
file:human/SOX9/SOX9-goa.tsv
GO:0045944 positive regulation of transcription by RNA polymerase II biological_process ECO:0000314 IDA PMID:22110751
|
|
GO:0046322
negative regulation of fatty acid oxidation
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Deep research mentions low lipid levels promote SOX9 expression and chondrogenic
commitment, with SOX9 suppressing fatty acid oxidation.
Reason: While documented, this represents a metabolic coupling to chondrogenic commitment
rather than a core transcription factor function. Peripheral metabolic effect.
Supporting Evidence:
file:human/SOX9/SOX9-uniprot.txt
when lipids levels are low, FOXO (FOXO1 and FOXO3) transcription factors promote expression of SOX9, which induces chondrogenic commitment and suppresses fatty acid oxidation
|
|
GO:0051216
cartilage development
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Broad parent term for cartilage development. SOX9 is the master regulator of
cartilage development.
Reason: This is a core biological process for SOX9. While less specific than chondrocyte
differentiation, it accurately captures SOX9's role in cartilage biology.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
orchestrate chondrogenesis
|
|
GO:0060009
Sertoli cell development
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: SOX9 is critical for Sertoli cell development and sex determination.
Reason: Sex determination and Sertoli cell development are important biological functions
of SOX9 but peripheral to the core cartilage/glial roles.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
Sex determination (testis development, Sertoli cell differentiation)
|
|
GO:0060174
limb bud formation
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: SOX9 is involved in limb skeletal development.
Reason: Limb development involves SOX9's chondrogenic function but this specific term
represents a developmental context rather than core molecular function.
|
|
GO:0070168
negative regulation of biomineral tissue development
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: SOX9 inhibits bone mineralization, maintaining cartilage. Has IDA evidence
(PMID:22110751).
Reason: This is part of SOX9's mechanism for maintaining cartilage identity by preventing
premature mineralization and osteoblast differentiation.
Supporting Evidence:
file:human/SOX9/SOX9-goa.tsv
GO:0070168 negative regulation of biomineral tissue development biological_process ECO:0000314 IDA PMID:22110751
|
|
GO:0070371
ERK1 and ERK2 cascade
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: SOX9 is involved in ERK signaling cascades in epithelial contexts.
Reason: ERK cascade involvement is context-specific (EGFR-ERK-SOX9 in urothelium) and
peripheral to core functions.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
An EGFR-ERK-SOX9 signaling cascade
|
|
GO:0070542
response to fatty acid
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Related to the lipid/fatty acid oxidation effects noted earlier.
Reason: Peripheral metabolic response, not core transcription factor function.
|
|
GO:0071260
cellular response to mechanical stimulus
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: SOX9 may respond to mechanical stimuli in cartilage contexts.
Reason: While potentially relevant to cartilage biology, this is a contextual response
rather than core molecular function.
|
|
GO:0071364
cellular response to epidermal growth factor stimulus
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: Related to EGFR signaling pathway involvement noted earlier.
Reason: Context-specific response in epithelial tissues, not core function.
|
|
GO:0071504
cellular response to heparin
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: SOX9 may respond to heparin in certain contexts.
Reason: Highly specific contextual response, unclear relevance to core functions.
|
|
GO:0071560
cellular response to transforming growth factor beta stimulus
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: SOX9 responds to TGF-beta signaling which regulates chondrogenesis. Has IDA
evidence (PMID:21401405).
Reason: TGF-beta signaling is central to chondrogenesis regulation. SOX9's response to
TGF-beta is part of its core chondrogenic program.
Supporting Evidence:
file:human/SOX9/SOX9-goa.tsv
GO:0071560 cellular response to transforming growth factor beta stimulus biological_process ECO:0000314 IDA PMID:21401405
|
|
GO:0071599
otic vesicle development
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: SOX9 is involved in inner ear development.
Reason: Peripheral developmental process in sensory organ development.
|
|
GO:0072034
renal vesicle induction
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: SOX9 regulates kidney development including renal vesicle formation.
Reason: Peripheral kidney development function.
|
|
GO:0072170
metanephric tubule development
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: SOX9 involved in kidney tubule development.
Reason: Peripheral kidney development function.
|
|
GO:0072190
ureter urothelium development
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: SOX9 regulates urothelial development.
Reason: Peripheral epithelial development.
|
|
GO:0090184
positive regulation of kidney development
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: SOX9 promotes kidney development.
Reason: Peripheral developmental function.
|
|
GO:0090190
positive regulation of branching involved in ureteric bud morphogenesis
|
IEA
GO_REF:0000107 |
KEEP AS NON CORE |
Summary: More specific kidney branching term.
Reason: Peripheral kidney development function.
|
|
GO:0097157
pre-mRNA intronic binding
|
IEA
GO_REF:0000107 |
UNDECIDED |
Summary: Deep research notes SOX9 regulates alternative splicing in beta cells, which may
involve intronic binding.
Reason: This is an interesting molecular function related to the alternative splicing
role discovered in beta cells, but unclear if this is broadly relevant to SOX9's
core functions.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
SOX9 persists in mature β cells and regulates alternative splicing programs
|
|
GO:1904864
negative regulation of beta-catenin-TCF complex assembly
|
IEA
GO_REF:0000107 |
ACCEPT |
Summary: SOX9 antagonizes beta-catenin by competing for binding sites with TCF/LEF factors.
Reason: This is a specific molecular mechanism by which SOX9 antagonizes Wnt signaling
to maintain chondrocyte identity. Part of core chondrogenic function.
Supporting Evidence:
file:human/SOX9/SOX9-uniprot.txt
Interacts with beta-catenin (CTNNB1); inhibiting CTNNB1 activity by competing with the binding sites of TCF/LEF within CTNNB1
|
|
GO:0005654
nucleoplasm
|
IDA
GO_REF:0000052 |
ACCEPT |
Summary: SOX9 localizes to nucleoplasm as a nuclear transcription factor.
Reason: Nucleoplasm is the appropriate sub-nuclear compartment for transcription factors.
More specific than just "nucleus."
Supporting Evidence:
file:human/SOX9/SOX9-goa.tsv
GO:0005654 nucleoplasm cellular_component ECO:0000314 IDA GO_REF:0000052
|
|
GO:0000122
negative regulation of transcription by RNA polymerase II
|
IMP
PMID:24014021 miR-1247 functions by targeting cartilage transcription fact... |
ACCEPT |
Summary: Duplicate of earlier IBA annotation with additional IMP evidence.
Reason: SOX9 has documented repressive functions. Multiple evidence codes support.
Supporting Evidence:
file:human/SOX9/SOX9-goa.tsv
GO:0000122 negative regulation of transcription by RNA polymerase II biological_process ECO:0000315 IMP PMID:24014021
PMID:24014021
2013 Sep 6. miR-1247 functions by targeting cartilage transcription factor SOX9.
|
|
GO:0001228
DNA-binding transcription activator activity, RNA polymerase II-specific
|
IDA
PMID:21367821 Sox9 sustains chondrocyte survival and hypertrophy in part t... |
ACCEPT |
Summary: Duplicate with IDA evidence from different publication.
Reason: Core molecular function with strong experimental support.
Supporting Evidence:
PMID:21367821
Sox9 sustains chondrocyte survival and hypertrophy in part through Pik3ca-Akt pathways.
|
|
GO:0045944
positive regulation of transcription by RNA polymerase II
|
IMP
PMID:21367821 Sox9 sustains chondrocyte survival and hypertrophy in part t... |
ACCEPT |
Summary: Duplicate with IMP evidence.
Reason: Core function with experimental evidence.
Supporting Evidence:
PMID:21367821
Sox9 sustains chondrocyte survival and hypertrophy in part through Pik3ca-Akt pathways.
|
|
GO:0000978
RNA polymerase II cis-regulatory region sequence-specific DNA binding
|
IDA
PMID:22110751 Inhibitory role of Notch1 in calcific aortic valve disease. |
ACCEPT |
Summary: Duplicate with IDA evidence from heart valve study.
Reason: Core molecular function.
Supporting Evidence:
PMID:22110751
Inhibitory role of Notch1 in calcific aortic valve disease.
|
|
GO:0001228
DNA-binding transcription activator activity, RNA polymerase II-specific
|
IDA
PMID:22110751 Inhibitory role of Notch1 in calcific aortic valve disease. |
ACCEPT |
Summary: Another duplicate with IDA evidence.
Reason: Core molecular function.
Supporting Evidence:
PMID:22110751
Inhibitory role of Notch1 in calcific aortic valve disease.
|
|
GO:0003180
aortic valve morphogenesis
|
IDA
PMID:22110751 Inhibitory role of Notch1 in calcific aortic valve disease. |
KEEP AS NON CORE |
Summary: Specific heart valve development term with experimental evidence.
Reason: Heart valve morphogenesis is peripheral to core cartilage/glial functions.
Supporting Evidence:
file:human/SOX9/SOX9-goa.tsv
GO:0003180 aortic valve morphogenesis biological_process ECO:0000314 IDA PMID:22110751
PMID:22110751
Inhibitory role of Notch1 in calcific aortic valve disease.
|
|
GO:0045944
positive regulation of transcription by RNA polymerase II
|
IDA
PMID:22110751 Inhibitory role of Notch1 in calcific aortic valve disease. |
ACCEPT |
Summary: Another duplicate from heart valve study.
Reason: Core function.
Supporting Evidence:
PMID:22110751
Inhibitory role of Notch1 in calcific aortic valve disease.
|
|
GO:0070168
negative regulation of biomineral tissue development
|
IDA
PMID:22110751 Inhibitory role of Notch1 in calcific aortic valve disease. |
ACCEPT |
Summary: Duplicate of earlier annotation with IDA evidence from heart valve study.
Reason: Part of core mechanism for maintaining cartilage over bone.
Supporting Evidence:
PMID:22110751
Inhibitory role of Notch1 in calcific aortic valve disease.
|
|
GO:0000981
DNA-binding transcription factor activity, RNA polymerase II-specific
|
IDA
PMID:20484372 The dimerization domain of SOX9 is required for transcriptio... |
ACCEPT |
Summary: Multiple IDA evidence codes from different publications.
Reason: Core molecular function.
Supporting Evidence:
PMID:20484372
May 19. The dimerization domain of SOX9 is required for transcription activation of a chondrocyte-specific chromatin DNA template.
|
|
GO:0000981
DNA-binding transcription factor activity, RNA polymerase II-specific
|
IDA
PMID:21412441 Failure of SOX9 regulation in 46XY disorders of sex developm... |
ACCEPT |
Summary: Another IDA evidence from sex determination study.
Reason: Core molecular function.
Supporting Evidence:
PMID:21412441
Failure of SOX9 regulation in 46XY disorders of sex development with SRY, SOX9 and SF1 mutations.
|
|
GO:0001228
DNA-binding transcription activator activity, RNA polymerase II-specific
|
IDA
PMID:20484372 The dimerization domain of SOX9 is required for transcriptio... |
ACCEPT |
Summary: Duplicate IDA evidence.
Reason: Core molecular function.
Supporting Evidence:
PMID:20484372
May 19. The dimerization domain of SOX9 is required for transcription activation of a chondrocyte-specific chromatin DNA template.
|
|
GO:0001228
DNA-binding transcription activator activity, RNA polymerase II-specific
|
IDA
PMID:20530484 SOX9, through interaction with microphthalmia-associated tra... |
ACCEPT |
Summary: Another IDA evidence.
Reason: Core molecular function.
Supporting Evidence:
PMID:20530484
Epub 2010 Jun 8. SOX9, through interaction with microphthalmia-associated transcription factor (MITF) and OTX2, regulates BEST1 expression in the retinal pigment epithelium.
|
|
GO:1902894
negative regulation of miRNA transcription
|
IDA
PMID:26687115 The microRNA-29 family in cartilage homeostasis and osteoart... |
KEEP AS NON CORE |
Summary: SOX9 regulates miRNA expression in cartilage contexts.
Reason: While experimentally validated, miRNA regulation is a secondary regulatory
mechanism rather than core transcription factor function.
Supporting Evidence:
file:human/SOX9/SOX9-goa.tsv
GO:1902894 negative regulation of miRNA transcription biological_process ECO:0000314 IDA PMID:26687115
PMID:26687115
2015 Dec 19. The microRNA-29 family in cartilage homeostasis and osteoarthritis.
|
|
GO:1990837
sequence-specific double-stranded DNA binding
|
IDA
PMID:28473536 Impact of cytosine methylation on DNA binding specificities ... |
ACCEPT |
Summary: Duplicate of earlier IEA annotation with IDA evidence.
Reason: Core molecular function with experimental support.
Supporting Evidence:
PMID:28473536
Impact of cytosine methylation on DNA binding specificities of human transcription factors.
|
|
GO:0001228
DNA-binding transcription activator activity, RNA polymerase II-specific
|
IDA
PMID:31194875 The SOXE transcription factors-SOX8, SOX9 and SOX10-share a ... |
ACCEPT |
Summary: More IDA evidence from transactivation domain study.
Reason: Core molecular function.
Supporting Evidence:
PMID:31194875
The SOXE transcription factors-SOX8, SOX9 and SOX10-share a bi-partite transactivation mechanism.
|
|
GO:0043565
sequence-specific DNA binding
|
IDA
PMID:31194875 The SOXE transcription factors-SOX8, SOX9 and SOX10-share a ... |
ACCEPT |
Summary: Duplicate with IDA evidence.
Reason: Core molecular function.
Supporting Evidence:
PMID:31194875
The SOXE transcription factors-SOX8, SOX9 and SOX10-share a bi-partite transactivation mechanism.
|
|
GO:0002062
chondrocyte differentiation
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Multiple evidence codes for this core function.
Reason: Core function with ISS evidence.
|
|
GO:0003430
growth plate cartilage chondrocyte growth
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Duplicate with ISS evidence.
Reason: Part of core chondrogenic program.
|
|
GO:0045668
negative regulation of osteoblast differentiation
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Duplicate with ISS evidence.
Reason: Core mechanism for maintaining chondrocyte identity.
|
|
GO:0046322
negative regulation of fatty acid oxidation
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Duplicate with ISS evidence.
Reason: Peripheral metabolic effect.
|
|
GO:0070542
response to fatty acid
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Duplicate with ISS evidence.
Reason: Peripheral metabolic response.
|
|
GO:0000785
chromatin
|
ISA
GO_REF:0000113 |
ACCEPT |
Summary: SOX9 binds chromatin as a transcription factor. Deep research notes it can act
as a pioneer factor at super-enhancers.
Reason: Chromatin localization is appropriate for a transcription factor that engages
enhancers and promoters.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
Can act as a pioneer factor at super-enhancers
|
|
GO:0000981
DNA-binding transcription factor activity, RNA polymerase II-specific
|
ISA
GO_REF:0000113 |
ACCEPT |
Summary: ISA evidence from TFClass database.
Reason: Core molecular function supported by database annotation.
|
|
GO:0010628
positive regulation of gene expression
|
IDA
PMID:24681825 The NLR-related protein NWD1 is associated with prostate can... |
ACCEPT |
Summary: Duplicate with IDA evidence.
Reason: Core transcriptional activator function.
Supporting Evidence:
PMID:24681825
The NLR-related protein NWD1 is associated with prostate cancer and modulates androgen receptor signaling.
|
|
GO:0005515
protein binding
|
IPI
PMID:28263186 Loss of DDRGK1 modulates SOX9 ubiquitination in spondyloepim... |
REMOVE |
Summary: Another generic protein binding annotation (DDRGK1 interaction).
Reason: Generic protein binding term. While DDRGK1 interaction affects SOX9 ubiquitination,
the generic term doesn't convey functional information.
Supporting Evidence:
PMID:28263186
Mar 6. Loss of DDRGK1 modulates SOX9 ubiquitination in spondyloepimetaphyseal dysplasia.
|
|
GO:0005634
nucleus
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Multiple evidence codes for nuclear localization.
Reason: Well-established cellular component.
|
|
GO:0005634
nucleus
|
IDA
PMID:26634652 Valve Endothelial Cell-Derived Tgfβ1 Signaling Promotes Nucl... |
ACCEPT |
Summary: IDA evidence for nuclear localization.
Reason: Well-established with experimental evidence.
Supporting Evidence:
PMID:26634652
Valve Endothelial Cell-Derived Tgfβ1 Signaling Promotes Nuclear Localization of Sox9 in Interstitial Cells Associated With Attenuated Calcification.
|
|
GO:0000978
RNA polymerase II cis-regulatory region sequence-specific DNA binding
|
IDA
PMID:20530484 SOX9, through interaction with microphthalmia-associated tra... |
ACCEPT |
Summary: Another IDA evidence.
Reason: Core molecular function.
Supporting Evidence:
PMID:20530484
Epub 2010 Jun 8. SOX9, through interaction with microphthalmia-associated transcription factor (MITF) and OTX2, regulates BEST1 expression in the retinal pigment epithelium.
|
|
GO:0061036
positive regulation of cartilage development
|
IDA
PMID:29503843 Sox9 augments BMP2-induced chondrogenic differentiation by d... |
ACCEPT |
Summary: SOX9 promotes cartilage development with IDA evidence.
Reason: This is essentially a parent term encompassing SOX9's chondrogenic functions.
Core function.
Supporting Evidence:
file:human/SOX9/SOX9-goa.tsv
GO:0061036 positive regulation of cartilage development biological_process ECO:0000314 IDA PMID:29503843
PMID:29503843
Nov 2. Sox9 augments BMP2-induced chondrogenic differentiation by downregulating Smad7 in mesenchymal stem cells (MSCs).
|
|
GO:1902732
positive regulation of chondrocyte proliferation
|
IDA
PMID:29503843 Sox9 augments BMP2-induced chondrogenic differentiation by d... |
ACCEPT |
Summary: SOX9 promotes chondrocyte proliferation in growth plate.
Reason: Part of core chondrogenic program maintaining columnar proliferation.
Supporting Evidence:
file:human/SOX9/SOX9-uniprot.txt
maintains chondrocyte columnar proliferation
PMID:29503843
Nov 2. Sox9 augments BMP2-induced chondrogenic differentiation by downregulating Smad7 in mesenchymal stem cells (MSCs).
|
|
GO:0030279
negative regulation of ossification
|
IDA
PMID:29503843 Sox9 augments BMP2-induced chondrogenic differentiation by d... |
ACCEPT |
Summary: Duplicate with IDA evidence.
Reason: Part of core mechanism.
Supporting Evidence:
PMID:29503843
Nov 2. Sox9 augments BMP2-induced chondrogenic differentiation by downregulating Smad7 in mesenchymal stem cells (MSCs).
|
|
GO:0000122
negative regulation of transcription by RNA polymerase II
|
IDA
PMID:29503843 Sox9 augments BMP2-induced chondrogenic differentiation by d... |
ACCEPT |
Summary: More IDA evidence for repressive function.
Reason: Documented repressive capability.
Supporting Evidence:
PMID:29503843
Nov 2. Sox9 augments BMP2-induced chondrogenic differentiation by downregulating Smad7 in mesenchymal stem cells (MSCs).
|
|
GO:0001502
cartilage condensation
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: SOX9 is absolutely required for precartilaginous condensation, the first step
in chondrogenesis.
Reason: Cartilage condensation is the initial step in chondrogenesis where SOX9 is
absolutely required. This is core chondrogenic function.
Supporting Evidence:
file:human/SOX9/SOX9-uniprot.txt
Absolutely required for precartilaginous condensation, the first step in chondrogenesis
|
|
GO:0014036
neural crest cell fate specification
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: SOX9 is involved in neural crest development.
Reason: Neural crest fate specification is peripheral to core cartilage/glial functions.
While SOX9 may affect neural crest, this is not its primary role.
|
|
GO:0071773
cellular response to BMP stimulus
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: SOX9 responds to BMP signaling which regulates chondrogenesis.
Reason: BMP signaling is central to chondrogenesis and SOX9 is a key effector of BMP
responses in cartilage differentiation.
Supporting Evidence:
file:human/SOX9/SOX9-uniprot.txt
Acts in cooperation with the Hedgehog pathway-dependent GLI (GLI1 and GLI3) transcription factors
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-5626938 |
ACCEPT |
Summary: Duplicate nucleoplasm annotation from Reactome.
Reason: Appropriate sub-nuclear compartment.
|
|
GO:0005654
nucleoplasm
|
TAS
Reactome:R-HSA-8985343 |
ACCEPT |
Summary: Another Reactome TAS annotation for nucleoplasm.
Reason: Appropriate sub-nuclear compartment.
|
|
GO:0032332
positive regulation of chondrocyte differentiation
|
IDA
PMID:21401405 Electroporation-mediated transfer of SOX trio genes (SOX-5, ... |
ACCEPT |
Summary: More IDA evidence for core function.
Reason: Core chondrogenic function.
Supporting Evidence:
PMID:21401405
Oct 21. Electroporation-mediated transfer of SOX trio genes (SOX-5, SOX-6, and SOX-9) to enhance the chondrogenesis of mesenchymal stem cells.
|
|
GO:0061036
positive regulation of cartilage development
|
IDA
PMID:21401405 Electroporation-mediated transfer of SOX trio genes (SOX-5, ... |
ACCEPT |
Summary: Duplicate with IDA evidence.
Reason: Core chondrogenic function.
Supporting Evidence:
PMID:21401405
Oct 21. Electroporation-mediated transfer of SOX trio genes (SOX-5, SOX-6, and SOX-9) to enhance the chondrogenesis of mesenchymal stem cells.
|
|
GO:0071560
cellular response to transforming growth factor beta stimulus
|
IDA
PMID:21401405 Electroporation-mediated transfer of SOX trio genes (SOX-5, ... |
ACCEPT |
Summary: Duplicate with IDA evidence.
Reason: Part of core chondrogenic signaling response.
Supporting Evidence:
PMID:21401405
Oct 21. Electroporation-mediated transfer of SOX trio genes (SOX-5, SOX-6, and SOX-9) to enhance the chondrogenesis of mesenchymal stem cells.
|
|
GO:0003415
chondrocyte hypertrophy
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Duplicate with ISS evidence.
Reason: Core chondrogenic program.
|
|
GO:0003682
chromatin binding
|
IDA
PMID:20484372 The dimerization domain of SOX9 is required for transcriptio... |
ACCEPT |
Summary: SOX9 binds chromatin with IDA evidence.
Reason: Chromatin binding is a specific molecular function relevant to SOX9's role as a
transcription factor engaging chromatin.
Supporting Evidence:
file:human/SOX9/SOX9-goa.tsv
GO:0003682 chromatin binding molecular_function ECO:0000314 IDA PMID:20484372
PMID:20484372
May 19. The dimerization domain of SOX9 is required for transcription activation of a chondrocyte-specific chromatin DNA template.
|
|
GO:0006334
nucleosome assembly
|
IDA
PMID:20484372 The dimerization domain of SOX9 is required for transcriptio... |
KEEP AS NON CORE |
Summary: PMID:20484372 shows SOX9 dimerization is required for nucleosome assembly during
chondrocyte-specific transcription activation.
Reason: While experimentally supported, nucleosome assembly is a chromatin remodeling
mechanism rather than a core transcription factor function. It's part of the
mechanistic process but peripheral to the primary role.
Supporting Evidence:
file:human/SOX9/SOX9-goa.tsv
GO:0006334 nucleosome assembly biological_process ECO:0000314 IDA PMID:20484372
PMID:20484372
May 19. The dimerization domain of SOX9 is required for transcription activation of a chondrocyte-specific chromatin DNA template.
|
|
GO:0006338
chromatin remodeling
|
IDA
PMID:20484372 The dimerization domain of SOX9 is required for transcriptio... |
KEEP AS NON CORE |
Summary: SOX9 is involved in chromatin remodeling at target genes.
Reason: Chromatin remodeling is a mechanistic process supporting transcription activation
but not a core defining function of SOX9.
Supporting Evidence:
PMID:20484372
May 19. The dimerization domain of SOX9 is required for transcription activation of a chondrocyte-specific chromatin DNA template.
|
|
GO:0007173
epidermal growth factor receptor signaling pathway
|
ISS
PMID:21512138 An EGFR-ERK-SOX9 signaling cascade links urothelial developm... |
KEEP AS NON CORE |
Summary: Duplicate with ISS evidence.
Reason: Context-specific signaling in epithelial tissues.
Supporting Evidence:
PMID:21512138
Epub 2011 Apr 21. An EGFR-ERK-SOX9 signaling cascade links urothelial development and regeneration to cancer.
|
|
GO:0008284
positive regulation of cell population proliferation
|
IMP
PMID:20651055 Upregulation of SOX9 in lung adenocarcinoma and its involvem... |
KEEP AS NON CORE |
Summary: SOX9 promotes proliferation in certain contexts (lung adenocarcinoma study).
Reason: While SOX9 does promote chondrocyte proliferation (core function), this generic
proliferation term from a cancer study represents peripheral effects rather than
the specific chondrocyte proliferation that is core.
Supporting Evidence:
PMID:20651055
Upregulation of SOX9 in lung adenocarcinoma and its involvement in the regulation of cell growth and tumorigenicity.
|
|
GO:0010634
positive regulation of epithelial cell migration
|
IMP
PMID:21512138 An EGFR-ERK-SOX9 signaling cascade links urothelial developm... |
KEEP AS NON CORE |
Summary: SOX9 promotes epithelial cell migration in urothelial contexts.
Reason: Context-specific epithelial function, not core cartilage/glial role.
Supporting Evidence:
PMID:21512138
Epub 2011 Apr 21. An EGFR-ERK-SOX9 signaling cascade links urothelial development and regeneration to cancer.
|
|
GO:0045892
negative regulation of DNA-templated transcription
|
IMP
PMID:20651055 Upregulation of SOX9 in lung adenocarcinoma and its involvem... |
ACCEPT |
Summary: General transcriptional repression term with IMP evidence.
Reason: SOX9 has documented repressive functions. More specific RNA Pol II term is
preferred but this is acceptable.
Supporting Evidence:
PMID:20651055
Upregulation of SOX9 in lung adenocarcinoma and its involvement in the regulation of cell growth and tumorigenicity.
|
|
GO:0045893
positive regulation of DNA-templated transcription
|
IMP
PMID:20651055 Upregulation of SOX9 in lung adenocarcinoma and its involvem... |
ACCEPT |
Summary: General transcriptional activation term with IMP evidence.
Reason: SOX9 is primarily a transcriptional activator. More specific RNA Pol II term is
preferred but this is acceptable.
Supporting Evidence:
PMID:20651055
Upregulation of SOX9 in lung adenocarcinoma and its involvement in the regulation of cell growth and tumorigenicity.
|
|
GO:0070371
ERK1 and ERK2 cascade
|
ISS
PMID:21512138 An EGFR-ERK-SOX9 signaling cascade links urothelial developm... |
KEEP AS NON CORE |
Summary: Duplicate ISS evidence.
Reason: Context-specific signaling.
Supporting Evidence:
PMID:21512138
Epub 2011 Apr 21. An EGFR-ERK-SOX9 signaling cascade links urothelial development and regeneration to cancer.
|
|
GO:0071260
cellular response to mechanical stimulus
|
ISS
PMID:21512138 An EGFR-ERK-SOX9 signaling cascade links urothelial developm... |
KEEP AS NON CORE |
Summary: Duplicate ISS evidence.
Reason: Context-specific response.
Supporting Evidence:
PMID:21512138
Epub 2011 Apr 21. An EGFR-ERK-SOX9 signaling cascade links urothelial development and regeneration to cancer.
|
|
GO:0071364
cellular response to epidermal growth factor stimulus
|
ISS
PMID:21512138 An EGFR-ERK-SOX9 signaling cascade links urothelial developm... |
KEEP AS NON CORE |
Summary: Duplicate ISS evidence.
Reason: Context-specific response.
Supporting Evidence:
PMID:21512138
Epub 2011 Apr 21. An EGFR-ERK-SOX9 signaling cascade links urothelial development and regeneration to cancer.
|
|
GO:0071504
cellular response to heparin
|
ISS
PMID:21512138 An EGFR-ERK-SOX9 signaling cascade links urothelial developm... |
KEEP AS NON CORE |
Summary: Duplicate ISS evidence.
Reason: Context-specific response.
Supporting Evidence:
PMID:21512138
Epub 2011 Apr 21. An EGFR-ERK-SOX9 signaling cascade links urothelial development and regeneration to cancer.
|
|
GO:2000020
positive regulation of male gonad development
|
IDA
PMID:21412441 Failure of SOX9 regulation in 46XY disorders of sex developm... |
KEEP AS NON CORE |
Summary: SOX9 promotes testis development with IDA evidence.
Reason: Sex determination is an important SOX9 function but peripheral to core cartilage/glial
roles.
Supporting Evidence:
PMID:21412441
Failure of SOX9 regulation in 46XY disorders of sex development with SRY, SOX9 and SF1 mutations.
|
|
GO:2000741
positive regulation of mesenchymal stem cell differentiation
|
IDA
PMID:21401405 Electroporation-mediated transfer of SOX trio genes (SOX-5, ... |
ACCEPT |
Summary: SOX9 promotes MSC differentiation toward chondrocytes.
Reason: MSC differentiation toward chondrocytes is part of the chondrogenic program.
This captures an earlier step in the lineage commitment.
Supporting Evidence:
PMID:21401405
Oct 21. Electroporation-mediated transfer of SOX trio genes (SOX-5, SOX-6, and SOX-9) to enhance the chondrogenesis of mesenchymal stem cells.
|
|
GO:0000987
cis-regulatory region sequence-specific DNA binding
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Duplicate with ISS evidence.
Reason: Core molecular function.
|
|
GO:0001502
cartilage condensation
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Duplicate ISS evidence.
Reason: Core first step in chondrogenesis.
|
|
GO:0001894
tissue homeostasis
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Duplicate ISS evidence.
Reason: Peripheral maintenance function.
|
|
GO:0002683
negative regulation of immune system process
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Duplicate ISS evidence.
Reason: Peripheral immunomodulatory effect.
|
|
GO:0003170
heart valve development
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Duplicate ISS evidence.
Reason: Peripheral developmental function.
|
|
GO:0030279
negative regulation of ossification
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Duplicate ISS evidence.
Reason: Core mechanism for maintaining cartilage.
|
|
GO:0030850
prostate gland development
|
IEP
PMID:20103652 SOX9 elevation in the prostate promotes proliferation and co... |
KEEP AS NON CORE |
Summary: IEP evidence for prostate development.
Reason: Peripheral epithelial development.
Supporting Evidence:
PMID:20103652
2010 Jan 26. SOX9 elevation in the prostate promotes proliferation and cooperates with PTEN loss to drive tumor formation.
|
|
GO:0050679
positive regulation of epithelial cell proliferation
|
IEP
PMID:20103652 SOX9 elevation in the prostate promotes proliferation and co... |
KEEP AS NON CORE |
Summary: IEP evidence from prostate study.
Reason: Context-specific epithelial proliferation, not core function.
Supporting Evidence:
PMID:20103652
2010 Jan 26. SOX9 elevation in the prostate promotes proliferation and cooperates with PTEN loss to drive tumor formation.
|
|
GO:0070168
negative regulation of biomineral tissue development
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Duplicate ISS evidence.
Reason: Core mechanism for maintaining cartilage.
|
|
GO:0071347
cellular response to interleukin-1
|
IEP
PMID:20079164 Interleukin-1 inhibits Sox9 and collagen type II expression ... |
KEEP AS NON CORE |
Summary: SOX9 responds to IL-1 in intervertebral disc cells.
Reason: Context-specific response in pathological conditions, not core function.
Supporting Evidence:
PMID:20079164
Interleukin-1 inhibits Sox9 and collagen type II expression via nuclear factor-kappaB in the cultured human intervertebral disc cells.
|
|
GO:0001708
cell fate specification
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: SOX9 specifies cell fates including chondrocyte, glial, and Sertoli cell fates.
Reason: Cell fate specification is fundamental to SOX9's function as a lineage-determining
transcription factor in chondrocytes and glia. This is core.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
essential for lineage specification... glial fate specification
|
|
GO:0001837
epithelial to mesenchymal transition
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: SOX9 is involved in EMT in various developmental contexts.
Reason: EMT is a process that occurs in multiple developmental contexts but is not a
core defining function of SOX9.
|
|
GO:0001942
hair follicle development
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: SOX9 plays roles in hair follicle development.
Reason: Hair follicle development is peripheral epithelial function noted in deep research
as one of multiple other programs.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
Hair follicle morphogenesis
|
|
GO:0002053
positive regulation of mesenchymal cell proliferation
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: SOX9 promotes mesenchymal cell proliferation.
Reason: While related to chondrogenesis (mesenchymal condensation), this generic
proliferation term is broader than the specific chondrocyte proliferation that
is core.
|
|
GO:0003179
heart valve morphogenesis
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Duplicate ISS evidence for heart valve.
Reason: Peripheral developmental function.
|
|
GO:0003203
endocardial cushion morphogenesis
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: SOX9 involved in heart cushion development.
Reason: Peripheral cardiac development function.
|
|
GO:0005634
nucleus
|
IDA
PMID:12420222 RAR agonists stimulate SOX9 gene expression in breast cancer... |
ACCEPT |
Summary: Multiple IDA evidence codes for nuclear localization.
Reason: Well-established with experimental evidence.
Supporting Evidence:
PMID:12420222
RAR agonists stimulate SOX9 gene expression in breast cancer cell lines: evidence for a role in retinoid-mediated growth inhibition.
|
|
GO:0007283
spermatogenesis
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: SOX9 involved in spermatogenesis via Sertoli cell function.
Reason: Peripheral reproductive developmental function.
|
|
GO:0010564
regulation of cell cycle process
|
IMP
PMID:12420222 RAR agonists stimulate SOX9 gene expression in breast cancer... |
KEEP AS NON CORE |
Summary: SOX9 can regulate cell cycle in certain contexts.
Reason: While SOX9 affects proliferation in chondrocytes, this generic cell cycle term
is overly broad and not a core defining function.
Supporting Evidence:
PMID:12420222
RAR agonists stimulate SOX9 gene expression in breast cancer cell lines: evidence for a role in retinoid-mediated growth inhibition.
|
|
GO:0019100
male germ-line sex determination
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: SOX9 is critical for male sex determination.
Reason: Important but peripheral to core cartilage/glial functions.
|
|
GO:0030858
positive regulation of epithelial cell differentiation
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: SOX9 promotes epithelial differentiation in multiple organs.
Reason: Generic epithelial differentiation is peripheral to core functions.
|
|
GO:0030916
otic vesicle formation
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: SOX9 involved in inner ear development.
Reason: Peripheral sensory organ development.
|
|
GO:0032331
negative regulation of chondrocyte differentiation
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: SOX9 can negatively regulate chondrocyte differentiation at certain stages to
maintain progenitor populations.
Reason: This reflects SOX9's context-dependent role in maintaining chondrocyte progenitors
versus promoting differentiation. Part of the nuanced chondrogenic program.
|
|
GO:0035019
somatic stem cell population maintenance
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: SOX9 maintains stem cell populations in various tissues.
Reason: While SOX9 can maintain stem/progenitor populations, this generic term doesn't
capture the core cartilage/glial functions.
|
|
GO:0042127
regulation of cell population proliferation
|
ISS
GO_REF:0000024 |
MARK AS OVER ANNOTATED |
Summary: Very generic proliferation regulation term.
Reason: Too generic to be informative. More specific terms about chondrocyte proliferation
are preferred.
|
|
GO:0042981
regulation of apoptotic process
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: SOX9 may regulate apoptosis in certain contexts.
Reason: Apoptosis regulation is a peripheral effect, not a core transcription factor
function.
|
|
GO:0043066
negative regulation of apoptotic process
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: SOX9 may have anti-apoptotic effects.
Reason: Peripheral effect, not core function.
|
|
GO:0045662
negative regulation of myoblast differentiation
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: SOX9 inhibits myoblast differentiation.
Reason: While SOX9 promotes chondrocyte over other mesenchymal fates, myoblast inhibition
is a peripheral effect.
|
|
GO:0046533
negative regulation of photoreceptor cell differentiation
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: SOX9 involved in retinal development.
Reason: Peripheral retinal development function.
|
|
GO:0050679
positive regulation of epithelial cell proliferation
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Duplicate ISS evidence.
Reason: Context-specific epithelial proliferation.
|
|
GO:0050680
negative regulation of epithelial cell proliferation
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: SOX9 can also negatively regulate epithelial proliferation contextually.
Reason: Context-dependent epithelial regulation, peripheral function.
|
|
GO:0051216
cartilage development
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: Duplicate ISS evidence.
Reason: Core chondrogenic function.
|
|
GO:0060008
Sertoli cell differentiation
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: SOX9 promotes Sertoli cell differentiation.
Reason: Peripheral sex determination function.
|
|
GO:0060041
retina development in camera-type eye
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: SOX9 involved in retinal development.
Reason: Peripheral sensory organ development.
|
|
GO:0060221
retinal rod cell differentiation
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: More specific retinal development term.
Reason: Peripheral sensory cell differentiation.
|
|
GO:0060517
epithelial cell proliferation involved in prostatic bud elongation
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Highly specific prostate development term.
Reason: Very specific peripheral developmental process.
|
|
GO:0060729
intestinal epithelial structure maintenance
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: SOX9 maintains intestinal epithelium.
Reason: Peripheral tissue maintenance function.
|
|
GO:0060784
regulation of cell proliferation involved in tissue homeostasis
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Generic tissue homeostasis proliferation regulation.
Reason: Peripheral maintenance function.
|
|
GO:0061138
morphogenesis of a branching epithelium
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Duplicate of earlier epithelial morphogenesis annotation.
Reason: Peripheral epithelial morphogenesis.
|
|
GO:0071300
cellular response to retinoic acid
|
IEP
PMID:12420222 RAR agonists stimulate SOX9 gene expression in breast cancer... |
KEEP AS NON CORE |
Summary: SOX9 responds to retinoic acid.
Reason: Contextual signaling response, not core function.
Supporting Evidence:
PMID:12420222
RAR agonists stimulate SOX9 gene expression in breast cancer cell lines: evidence for a role in retinoid-mediated growth inhibition.
|
|
GO:0072289
metanephric nephron tubule formation
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: More specific kidney development term.
Reason: Peripheral kidney development.
|
|
GO:0090090
negative regulation of canonical Wnt signaling pathway
|
ISS
GO_REF:0000024 |
ACCEPT |
Summary: SOX9 antagonizes Wnt/beta-catenin signaling.
Reason: Wnt/beta-catenin antagonism is a core mechanism by which SOX9 maintains chondrocyte
identity and blocks osteoblast differentiation.
Supporting Evidence:
file:human/SOX9/SOX9-deep-research-falcon.md
Antagonizes β-catenin in chondrocytes
|
|
GO:0090103
cochlea morphogenesis
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: SOX9 involved in inner ear cochlea development.
Reason: Peripheral sensory organ development.
|
|
GO:0001501
skeletal system development
|
IMP
PMID:8640233 Sex reversal by loss of the C-terminal transactivation domai... |
ACCEPT |
Summary: Broad term for skeletal development with IMP evidence from foundational SOX9
study.
Reason: Skeletal system development encompasses SOX9's chondrogenic functions. While
broad, this is a core developmental process for SOX9.
Supporting Evidence:
file:human/SOX9/SOX9-goa.tsv
GO:0001501 skeletal system development biological_process ECO:0000315 IMP PMID:8640233
PMID:8640233
Sex reversal by loss of the C-terminal transactivation domain of human SOX9.
|
|
GO:0003413
chondrocyte differentiation involved in endochondral bone morphogenesis
|
IMP
PMID:20676705 Generation of transgenic mice for conditional overexpression... |
ACCEPT |
Summary: More specific term for chondrocyte differentiation in context of endochondral
ossification.
Reason: This captures the specific developmental context where SOX9-driven chondrogenesis
creates the cartilage template for bone formation. Core function.
Supporting Evidence:
file:human/SOX9/SOX9-goa.tsv
GO:0003413 chondrocyte differentiation involved in endochondral bone morphogenesis biological_process ECO:0000315 IMP PMID:20676705
PMID:20676705
2010 Jul 30. Generation of transgenic mice for conditional overexpression of Sox9.
|
|
GO:0003700
DNA-binding transcription factor activity
|
IMP
PMID:8640233 Sex reversal by loss of the C-terminal transactivation domai... |
ACCEPT |
Summary: IMP evidence from foundational study.
Reason: Core molecular function with experimental evidence.
Supporting Evidence:
PMID:8640233
Sex reversal by loss of the C-terminal transactivation domain of human SOX9.
|
|
GO:0005634
nucleus
|
IDA
PMID:8640233 Sex reversal by loss of the C-terminal transactivation domai... |
ACCEPT |
Summary: More IDA evidence for nuclear localization.
Reason: Well-established cellular component.
Supporting Evidence:
PMID:8640233
Sex reversal by loss of the C-terminal transactivation domain of human SOX9.
|
|
GO:0008584
male gonad development
|
IMP
PMID:8640233 Sex reversal by loss of the C-terminal transactivation domai... |
KEEP AS NON CORE |
Summary: IMP evidence for testis development.
Reason: Peripheral sex determination function.
Supporting Evidence:
PMID:8640233
Sex reversal by loss of the C-terminal transactivation domain of human SOX9.
|
|
GO:0032332
positive regulation of chondrocyte differentiation
|
IMP
PMID:20676705 Generation of transgenic mice for conditional overexpression... |
ACCEPT |
Summary: More IMP evidence for core function.
Reason: Core chondrogenic function.
Supporting Evidence:
PMID:20676705
2010 Jul 30. Generation of transgenic mice for conditional overexpression of Sox9.
|
|
GO:0045944
positive regulation of transcription by RNA polymerase II
|
IDA
PMID:8640233 Sex reversal by loss of the C-terminal transactivation domai... |
ACCEPT |
Summary: IDA evidence from foundational study.
Reason: Core transcriptional activator function.
Supporting Evidence:
PMID:8640233
Sex reversal by loss of the C-terminal transactivation domain of human SOX9.
|
|
GO:0005634
nucleus
|
IDA
PMID:18512230 Quantitative assessment of glial cells in the human and guin... |
ACCEPT |
Summary: More IDA evidence for nucleus.
Reason: Well-established.
Supporting Evidence:
PMID:18512230
Quantitative assessment of glial cells in the human and guinea pig enteric nervous system with an anti-Sox8/9/10 antibody.
|
|
GO:0000987
cis-regulatory region sequence-specific DNA binding
|
IDA
PMID:10805756 Phosphorylation of SOX9 by cyclic AMP-dependent protein kina... |
ACCEPT |
Summary: IDA evidence for sequence-specific binding.
Reason: Core molecular function.
Supporting Evidence:
PMID:10805756
Phosphorylation of SOX9 by cyclic AMP-dependent protein kinase A enhances SOX9's ability to transactivate a Col2a1 chondrocyte-specific enhancer.
|
|
GO:0003700
DNA-binding transcription factor activity
|
IDA
PMID:10805756 Phosphorylation of SOX9 by cyclic AMP-dependent protein kina... |
ACCEPT |
Summary: More IDA evidence.
Reason: Core molecular function.
Supporting Evidence:
PMID:10805756
Phosphorylation of SOX9 by cyclic AMP-dependent protein kinase A enhances SOX9's ability to transactivate a Col2a1 chondrocyte-specific enhancer.
|
|
GO:0005515
protein binding
|
IPI
PMID:20530484 SOX9, through interaction with microphthalmia-associated tra... |
REMOVE |
Summary: Another generic protein binding (MITF/OTX2 interactions).
Reason: Generic protein binding term, uninformative.
Supporting Evidence:
PMID:20530484
Epub 2010 Jun 8. SOX9, through interaction with microphthalmia-associated transcription factor (MITF) and OTX2, regulates BEST1 expression in the retinal pigment epithelium.
|
|
GO:0005634
nucleus
|
IDA
PMID:10805756 Phosphorylation of SOX9 by cyclic AMP-dependent protein kina... |
ACCEPT |
Summary: More IDA evidence.
Reason: Well-established.
Supporting Evidence:
PMID:10805756
Phosphorylation of SOX9 by cyclic AMP-dependent protein kinase A enhances SOX9's ability to transactivate a Col2a1 chondrocyte-specific enhancer.
|
|
GO:0032991
protein-containing complex
|
IDA
PMID:20530484 SOX9, through interaction with microphthalmia-associated tra... |
MARK AS OVER ANNOTATED |
Summary: SOX9 forms complexes with partners. This is a very generic cellular component
term.
Reason: Too generic. More specific terms like "transcription regulator complex" better
capture SOX9's complex formation.
Supporting Evidence:
PMID:20530484
Epub 2010 Jun 8. SOX9, through interaction with microphthalmia-associated transcription factor (MITF) and OTX2, regulates BEST1 expression in the retinal pigment epithelium.
|
|
GO:0034236
protein kinase A catalytic subunit binding
|
IPI
PMID:10805756 Phosphorylation of SOX9 by cyclic AMP-dependent protein kina... |
ACCEPT |
Summary: SOX9 interacts with PKA which phosphorylates it to enhance activity. This is
a specific binding term.
Reason: PKA binding and phosphorylation is a specific regulatory mechanism for SOX9
activity. Unlike generic protein binding, this conveys functional information.
Supporting Evidence:
file:human/SOX9/SOX9-uniprot.txt
Phosphorylation at Ser-64 and Ser-211 by PKA increases transcriptional activity
PMID:10805756
Phosphorylation of SOX9 by cyclic AMP-dependent protein kinase A enhances SOX9's ability to transactivate a Col2a1 chondrocyte-specific enhancer.
|
|
GO:0045893
positive regulation of DNA-templated transcription
|
IDA
PMID:10805756 Phosphorylation of SOX9 by cyclic AMP-dependent protein kina... |
ACCEPT |
Summary: IDA evidence for transcriptional activation.
Reason: Core activator function.
Supporting Evidence:
PMID:10805756
Phosphorylation of SOX9 by cyclic AMP-dependent protein kinase A enhances SOX9's ability to transactivate a Col2a1 chondrocyte-specific enhancer.
|
|
GO:0045944
positive regulation of transcription by RNA polymerase II
|
IDA
PMID:20530484 SOX9, through interaction with microphthalmia-associated tra... |
ACCEPT |
Summary: More IDA evidence.
Reason: Core function.
Supporting Evidence:
PMID:20530484
Epub 2010 Jun 8. SOX9, through interaction with microphthalmia-associated transcription factor (MITF) and OTX2, regulates BEST1 expression in the retinal pigment epithelium.
|
|
GO:0065003
protein-containing complex assembly
|
IDA
PMID:20530484 SOX9, through interaction with microphthalmia-associated tra... |
KEEP AS NON CORE |
Summary: SOX9 assembles into protein complexes.
Reason: While SOX9 does form complexes, this generic assembly term doesn't capture the
core transcription factor function.
Supporting Evidence:
PMID:20530484
Epub 2010 Jun 8. SOX9, through interaction with microphthalmia-associated transcription factor (MITF) and OTX2, regulates BEST1 expression in the retinal pigment epithelium.
|
|
GO:0007165
signal transduction
|
ISS
GO_REF:0000024 |
MARK AS OVER ANNOTATED |
Summary: Duplicate of earlier very generic signal transduction term.
Reason: Too generic to be informative.
|
|
GO:0072034
renal vesicle induction
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Duplicate kidney development term.
Reason: Peripheral kidney development.
|
|
GO:0090184
positive regulation of kidney development
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Duplicate kidney development term.
Reason: Peripheral kidney development.
|
|
GO:0090190
positive regulation of branching involved in ureteric bud morphogenesis
|
ISS
GO_REF:0000024 |
KEEP AS NON CORE |
Summary: Duplicate kidney branching term.
Reason: Peripheral kidney development.
|
|
GO:0008584
male gonad development
|
IEP
PMID:17848411 Developmental changes in human fetal testicular cell numbers... |
KEEP AS NON CORE |
Summary: IEP evidence for testis development.
Reason: Peripheral sex determination function.
Supporting Evidence:
PMID:17848411
Epub 2007 Sep 11. Developmental changes in human fetal testicular cell numbers and messenger ribonucleic acid levels during the second trimester.
|
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model: Edison Scientific Literature
cached: false
start_time: '2026-01-11T23:22:02.393539'
end_time: '2026-01-11T23:29:30.996911'
duration_seconds: 448.6
template_file: templates/gene_research_go_focused.md
template_variables:
organism: human
gene_id: SOX9
gene_symbol: SOX9
uniprot_accession: P48436
protein_description: 'RecName: Full=Transcription factor SOX-9 {ECO:0000305};'
gene_info: Name=SOX9 {ECO:0000303|PubMed:7990924, ECO:0000312|HGNC:HGNC:11204};
organism_full: Homo sapiens (Human).
protein_family: Not specified in UniProt
protein_domains: HMG_box_dom. (IPR009071); HMG_box_dom_sf. (IPR036910); Sox_N. (IPR022151);
SOX_TF. (IPR050917); HMG_box (PF00505)
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BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.
DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'SOX9' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information
Please provide a comprehensive research report on the gene SOX9 (gene ID: SOX9, UniProt: P48436) in human.
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.
BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.
DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'SOX9' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information
Please provide a comprehensive research report on the gene SOX9 (gene ID: SOX9, UniProt: P48436) in human.
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
Title: Human SOX9 (UniProt P48436): molecular function, regulation, pathways, and recent translational developments
Abstract
SOX9 is a human SOXE-family transcription factor essential for lineage specification and tissue homeostasis. It binds AACAAT-centered motifs via its HMG-box, bends DNA, recruits co-activators, and often cooperates with SOX5/6 to orchestrate chondrogenesis and other organogenetic programs. Recent studies (2023–2024) refine enhancer control of Sox9 in chondrocytes, define injury- and context-specific roles in fibrosis and endothelial-to-mesenchymal transition, and uncover disease-relevant post-translational and metabolic couplings in cancer and liver disease. Here, we synthesize key concepts, new findings, applications, expert perspectives, and recent quantitative data.
Regulatory post-translational modifications (PTMs). Phosphorylation (including cAMP/PKA- and ERK-coupled events) and lysine acetylation/sumoylation modulate SOX9 DNA binding, nuclear import, and transactivation in cartilage contexts; ubiquitination and arginine methylation also contribute to turnover and pathway cross-talk (Cell Mol Life Sci, 2022; URL: https://doi.org/10.1007/s00018-022-04543-4; published Sep 2022) (lefebvre2017sox9andthe pages 19-22, ming2022sox9inorganogenesis pages 24-25).
Recent developments and latest research (2023–2024 priorities)
Fibrosis outside kidney: thyroid eye disease (2024). In primary orbital fibroblasts from patients with TED, SOX9 is upregulated; modulation of SOX9 shifts extracellular-matrix gene expression and contractility via MAPK/ERK1/2 signaling. SOX9 binds the EGFR promoter, nominating a SOX9–EGFR axis as a therapeutic target (Invest Ophthalmol Vis Sci, 2024; URL: https://doi.org/10.1167/iovs.65.2.25; published Feb 2024) (zhou2024sox9inducesorbital pages 1-2).
Current applications and real-world implementations
Regenerative medicine and cartilage engineering. Mechanistically precise enhancer control and SOX5/6 cooperation in chondrogenesis guide strategies to maintain hyaline cartilage identity in tissue engineering and repair (JCI Insight, 2024; URL: https://doi.org/10.1172/jci.insight.175486; published Jun 2024) (ichiyamakobayashi2024chromatinprofilingidentifies pages 1-2).
Expert opinions and analyses from authoritative sources
Fibrosis biology. Science 2024 provides a conceptual “SOX9 switch” model that explains divergent outcomes after injury and suggests tractable nodes (CDH6+ SOX9on-on and WNT ligands) for intervention in human kidneys (Science, 2024; URL: https://doi.org/10.1126/science.add6371; published Feb 2024) (aggarwal2024sox9switchlinks pages 1-3).
Relevant statistics and quantitative data
Mechanistic synthesis focused on primary function, localization, and pathways
- Primary function and DNA specificity. SOX9 binds an AACAAT-centered motif through its HMG box, bending DNA and enabling enhancer complex assembly. Cooperative binding with SOX5/6 at paired SOX sites underlies potent activation of cartilage matrix genes; recruitment of CBP/p300/TIP60 further enhances transactivation (Cell Mol Life Sci, 2022; URL: https://doi.org/10.1007/s00018-022-04543-4; published Sep 2022) (ming2022sox9inorganogenesis pages 19-20, ming2022sox9inorganogenesis pages 1-2).
- Subcellular site of action. SOX9 functions in the nucleus; nuclear import/export and transcriptional activity are modulated by phosphorylation and acetylation, integrating upstream signaling (Cell Mol Life Sci, 2022; URL: https://doi.org/10.1007/s00018-022-04543-4; published Sep 2022) (ming2022sox9inorganogenesis pages 24-25).
- PTM and metabolic coupling. Recent evidence couples tumor hypoxia and glycolysis to SOX9 function via protein lactylation in NSCLC, linking metabolic flux to SOX9-driven stemness and invasion (Cancer Biol Ther, 2024; URL: https://doi.org/10.1080/15384047.2024.2304161; accepted Jan 2024) (yan2024hypoxiapromotesnonsmall pages 1-2). In hepatocytes, SOX9 engages AMPK signaling to alleviate steatohepatitis (J Clin Transl Hepatol, 2024; URL: https://doi.org/10.14218/JCTH.2024.00197; published online Dec 20, 2024) (deng2024sox9overexpressionameliorates pages 1-2). In β cells, SOX9 controls alternative splicing programs required for insulin secretion (Nat Commun, 2024; URL: https://doi.org/10.1038/s41467-023-44384-8; published Jan 2024) (puri2024sox9regulatesalternative pages 1-2, puri2024sox9regulatesalternative pages 2-4).
- Core pathways. In chondrogenesis, SOX9 with SOX5/6 drives cartilage gene networks, and enhancer studies show Sox9 expression depends on multiple chondrocyte enhancers integrating BMP cues (JCI Insight, 2024; URL: https://doi.org/10.1172/jci.insight.175486; published Jun 2024) (ichiyamakobayashi2024chromatinprofilingidentifies pages 1-2). In injury/fibrosis, SOX9 acts as a repair sensor in kidney epithelia, with sustained activity eliciting WNT secretion and fibroblast activation (Science, 2024; URL: https://doi.org/10.1126/science.add6371; published Feb 2024) (aggarwal2024sox9switchlinks pages 1-3). In vascular contexts, oxLDL-induced EndMT is SOX9-dependent (Angiogenesis, 2024; URL: https://doi.org/10.1007/s10456-024-09927-7; published May 2024) (zhao2024distinctrolesof pages 1-2). In fibrotic orbit disease, SOX9 activates MAPK/ERK and targets EGFR (IOVS, 2024; URL: https://doi.org/10.1167/iovs.65.2.25; published Feb 2024) (zhou2024sox9inducesorbital pages 1-2).
Verification of target identity and avoidance of symbol ambiguity
- The synthesis above refers to human SOX9 (UniProt P48436) and vertebrate models used to resolve human SOX9 biology. Domain and binding properties match the UniProt description (HMG box; SOX transcription factor; enhancer-level regulation). Foundational reviews and 2024 studies align with the human gene symbol and organism context (Cell Mol Life Sci, 2022; JCI Insight, 2024) (ming2022sox9inorganogenesis pages 19-20, ichiyamakobayashi2024chromatinprofilingidentifies pages 1-2).
Limitations
- Some historically foundational mechanistic details (e.g., specific NLS mapping and individual phosphorylation sites) derive from earlier primary literature not captured in the 2023–2024 set. Where necessary, we referenced a 2022 expert review that consolidates these details. For campomelic dysplasia genetics and sex-determination enhancer modules, the 2024 chondrocyte enhancer work provides the most recent mechanistic update (JCI Insight, 2024) (ichiyamakobayashi2024chromatinprofilingidentifies pages 2-4, ichiyamakobayashi2024chromatinprofilingidentifies pages 1-2).
Conclusions
SOX9 functions as a nuclear, pioneer-like transcription factor that reads AACAAT-centered motifs to assemble lineage-defining enhancer programs with SOX5/6 and chromatin co-activators. 2023–2024 studies sharpen the regulatory map of Sox9 in chondrocytes, link injury-induced SOX9 dynamics to regenerative versus fibrotic outcomes in kidney, implicate SOX9 in oxLDL-driven EndMT and hypoxia-driven cancer plasticity, uncover a β-cell splicing role essential for insulin secretion, and reveal a protective SOX9–AMPK axis in MASH. These advances inform diagnostics (noncoding enhanceropathies), anti-fibrotic strategies (SOX9on-on/WNT blockade), metabolic disease interventions (AMPK), and oncology approaches targeting metabolic-epigenetic SOX9 activation.
References
(ming2022sox9inorganogenesis pages 19-20): Zhenhua Ming, Brittany Vining, Stefan Bagheri-Fam, and Vincent Harley. Sox9 in organogenesis: shared and unique transcriptional functions. Cellular and Molecular Life Sciences, Sep 2022. URL: https://doi.org/10.1007/s00018-022-04543-4, doi:10.1007/s00018-022-04543-4. This article has 85 citations and is from a domain leading peer-reviewed journal.
(ming2022sox9inorganogenesis pages 1-2): Zhenhua Ming, Brittany Vining, Stefan Bagheri-Fam, and Vincent Harley. Sox9 in organogenesis: shared and unique transcriptional functions. Cellular and Molecular Life Sciences, Sep 2022. URL: https://doi.org/10.1007/s00018-022-04543-4, doi:10.1007/s00018-022-04543-4. This article has 85 citations and is from a domain leading peer-reviewed journal.
(ichiyamakobayashi2024chromatinprofilingidentifies pages 1-2): Sachi Ichiyama-Kobayashi, Kenji Hata, Kanta Wakamori, Yoshifumi Takahata, Tomohiko Murakami, Hitomi Yamanaka, Hiroshi Takano, Ryoji Yao, Narikazu Uzawa, and Riko Nishimura. Chromatin profiling identifies chondrocyte-specific sox9 enhancers important for skeletal development. JCI Insight, Jun 2024. URL: https://doi.org/10.1172/jci.insight.175486, doi:10.1172/jci.insight.175486. This article has 8 citations and is from a domain leading peer-reviewed journal.
(ming2022sox9inorganogenesis pages 24-25): Zhenhua Ming, Brittany Vining, Stefan Bagheri-Fam, and Vincent Harley. Sox9 in organogenesis: shared and unique transcriptional functions. Cellular and Molecular Life Sciences, Sep 2022. URL: https://doi.org/10.1007/s00018-022-04543-4, doi:10.1007/s00018-022-04543-4. This article has 85 citations and is from a domain leading peer-reviewed journal.
(lefebvre2017sox9andthe pages 19-22): Véronique Lefebvre and Mona Dvir-Ginzberg. Sox9 and the many facets of its regulation in the chondrocyte lineage. Connective Tissue Research, 58:14-2, Jan 2017. URL: https://doi.org/10.1080/03008207.2016.1183667, doi:10.1080/03008207.2016.1183667. This article has 440 citations and is from a peer-reviewed journal.
(ichiyamakobayashi2024chromatinprofilingidentifies pages 2-4): Sachi Ichiyama-Kobayashi, Kenji Hata, Kanta Wakamori, Yoshifumi Takahata, Tomohiko Murakami, Hitomi Yamanaka, Hiroshi Takano, Ryoji Yao, Narikazu Uzawa, and Riko Nishimura. Chromatin profiling identifies chondrocyte-specific sox9 enhancers important for skeletal development. JCI Insight, Jun 2024. URL: https://doi.org/10.1172/jci.insight.175486, doi:10.1172/jci.insight.175486. This article has 8 citations and is from a domain leading peer-reviewed journal.
(aggarwal2024sox9switchlinks pages 1-3): Shikhar Aggarwal, Zhanxiang Wang, David Rincon Fernandez Pacheco, Anna Rinaldi, Alex Rajewski, Jasper Callemeyn, Elisabet Van Loon, Baptiste Lamarthée, Ambart Ester Covarrubias, Jean Hou, Michifumi Yamashita, Haruhiko Akiyama, S. Ananth Karumanchi, Clive N. Svendsen, Paul W. Noble, Stanley C. Jordan, Joshua J. Breunig, Maarten Naesens, Pietro E. Cippà, and Sanjeev Kumar. Sox9 switch links regeneration to fibrosis at the single-cell level in mammalian kidneys. Science, Feb 2024. URL: https://doi.org/10.1126/science.add6371, doi:10.1126/science.add6371. This article has 97 citations and is from a highest quality peer-reviewed journal.
(zhao2024distinctrolesof pages 1-2): Jilai Zhao, Laura Sormani, Sebastien Jacquelin, Haiming Li, Cassandra Styke, Chenhao Zhou, Jonathan Beesley, Linus Oon, Simranpreet Kaur, Seen-Ling Sim, Ho Yi Wong, James Dight, Ghazaleh Hashemi, Abbas Shafiee, Edwige Roy, Jatin Patel, and Kiarash Khosrotehrani. Distinct roles of sox9 in self-renewal of progenitors and mesenchymal transition of the endothelium. Angiogenesis, 27:545-560, May 2024. URL: https://doi.org/10.1007/s10456-024-09927-7, doi:10.1007/s10456-024-09927-7. This article has 2 citations and is from a domain leading peer-reviewed journal.
(yan2024hypoxiapromotesnonsmall pages 1-2): Fei Yan, Yue Teng, Xiaoyou Li, Yuejiao Zhong, Chunyi Li, Feng Yan, and Xia He. Hypoxia promotes non-small cell lung cancer cell stemness, migration, and invasion via promoting glycolysis by lactylation of sox9. Cancer Biology & Therapy, Jan 2024. URL: https://doi.org/10.1080/15384047.2024.2304161, doi:10.1080/15384047.2024.2304161. This article has 81 citations and is from a peer-reviewed journal.
(puri2024sox9regulatesalternative pages 1-2): Sapna Puri, Hasna Maachi, Gopika Nair, Holger A. Russ, Richard Chen, Pamela Pulimeno, Zachary Cutts, Vasilis Ntranos, and Matthias Hebrok. Sox9 regulates alternative splicing and pancreatic beta cell function. Nature Communications, Jan 2024. URL: https://doi.org/10.1038/s41467-023-44384-8, doi:10.1038/s41467-023-44384-8. This article has 17 citations and is from a highest quality peer-reviewed journal.
(puri2024sox9regulatesalternative pages 2-4): Sapna Puri, Hasna Maachi, Gopika Nair, Holger A. Russ, Richard Chen, Pamela Pulimeno, Zachary Cutts, Vasilis Ntranos, and Matthias Hebrok. Sox9 regulates alternative splicing and pancreatic beta cell function. Nature Communications, Jan 2024. URL: https://doi.org/10.1038/s41467-023-44384-8, doi:10.1038/s41467-023-44384-8. This article has 17 citations and is from a highest quality peer-reviewed journal.
(deng2024sox9overexpressionameliorates pages 1-2): Juan Deng, Kai Ding, Shuqing Liu, Fei Chen, Ru Huang, Bo-Nan Xu, Xin Zhang, and Wei-Fen Xie. Sox9 overexpression ameliorates metabolic dysfunction-associated steatohepatitis through activation of the ampk pathway. Journal of Clinical and Translational Hepatology, 13:189-199, Dec 2024. URL: https://doi.org/10.14218/jcth.2024.00197, doi:10.14218/jcth.2024.00197. This article has 1 citations.
(zhou2024sox9inducesorbital pages 1-2): Min Zhou, Bingying Lin, Pengsen Wu, Yu Ke, Siyu Huang, Fan Zhang, Xiangqing Hei, Zhen Mao, Xingyi Li, Pengxia Wan, Tingting Chen, Huasheng Yang, and Danping Huang. Sox9 induces orbital fibroblast activation in thyroid eye disease via mapk/erk1/2 pathway. Investigative Opthalmology & Visual Science, 65:25, Feb 2024. URL: https://doi.org/10.1167/iovs.65.2.25, doi:10.1167/iovs.65.2.25. This article has 11 citations.
id: P48436
gene_symbol: SOX9
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: |
SOX9 is a SOXE-family transcription factor that plays dual core roles in development.
First, SOX9 is the master regulator of chondrogenesis, cooperating with SOX5 and SOX6
to drive cartilage matrix gene expression (COL2A1, ACAN) and promoting chondrocyte
differentiation while antagonizing osteoblast differentiation via beta-catenin inhibition.
Second, SOX9 is critical for oligodendrocyte differentiation and glial fate specification,
promoting glial over neuronal fates in the CNS. SOX9 binds AACAAT-centered DNA motifs
via its HMG-box domain, bends DNA, and recruits co-activators CBP/p300 and TIP60. It
functions exclusively in the nucleus with nuclear localization and export signals.
Post-translational modifications including phosphorylation, acetylation, and sumoylation
regulate its activity. While SOX9 has additional developmental roles in sex determination,
heart valve, kidney, and other epithelial programs, its core molecular functions center
on transcriptional activation in cartilage and glial lineages.
existing_annotations:
- term:
id: GO:0000981
label: DNA-binding transcription factor activity, RNA polymerase II-specific
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: |
SOX9 is a bona fide RNA Pol II transcription factor with experimentally validated
DNA-binding and transactivation domains (deep research, UniProt). It binds the
AACAAT motif via HMG-box and activates transcription of cartilage and other target
genes.
action: ACCEPT
reason: |
This is a core molecular function of SOX9. The IBA annotation correctly captures
SOX9's role as an RNA Pol II-specific transcription factor, supported by extensive
experimental evidence showing DNA binding, transactivation, and regulation of Pol
II-transcribed genes.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: SOX9 is a human SOXE-family transcription factor
essential for lineage specification... binds AACAAT-centered motifs via
its HMG-box... recruits co-activators CBP/p300 and TIP60
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: 'model: Edison Scientific Literature'
- term:
id: GO:0002009
label: morphogenesis of an epithelium
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: |
SOX9 regulates epithelial morphogenesis in multiple organs including lung, kidney,
intestine, and prostate. Deep research notes roles in lung epithelium during
branching morphogenesis and kidney epithelial branching.
action: KEEP_AS_NON_CORE
reason: |
While well-supported, epithelial morphogenesis represents peripheral developmental
processes rather than the core chondrogenic and gliogenic transcription factor
functions of SOX9. This is a pleiotropic effect.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: involved in the lung epithelium during branching
morphogenesis... Controls epithelial branching during kidney development
- term:
id: GO:0005634
label: nucleus
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: |
SOX9 functions in the nucleus with validated nuclear localization signals and
nuclear export signals. UniProt describes nuclear localization, and deep research
confirms nuclear function.
action: ACCEPT
reason: |
Nuclear localization is essential for SOX9's transcription factor function. Multiple
lines of evidence support this including NLS/NES identification and experimental
demonstration of nuclear localization.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: SOX9 harbors nuclear localization and export signals...
SOX9 functions in the nucleus
- reference_id: file:human/SOX9/SOX9-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
id: GO:0007507
label: heart development
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: |
SOX9 is involved in heart valve development and aortic valve morphogenesis with
IDA evidence (PMID:22110751). GOA file shows multiple heart-related annotations.
action: KEEP_AS_NON_CORE
reason: |
Heart development is a legitimate but peripheral function of SOX9. The core
functions are chondrogenesis and gliogenesis. Heart valve development is a
pleiotropic effect.
supported_by:
- reference_id: file:human/SOX9/SOX9-goa.tsv
supporting_text: GO:0003180 aortic valve morphogenesis biological_process
ECO:0000314 IDA PMID:22110751
- term:
id: GO:0000122
label: negative regulation of transcription by RNA polymerase II
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: |
SOX9 can act as both activator and repressor. IMP evidence (PMID:24014021,
PMID:29503843) shows SOX9 can negatively regulate transcription. Deep research
notes SOX9 antagonizes beta-catenin.
action: ACCEPT
reason: |
SOX9 has documented repressive functions including inhibition of osteoblast genes
and antagonism of beta-catenin signaling. This is part of its core regulatory
mechanism in maintaining chondrocyte identity.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: Antagonizes β-catenin in chondrocytes... prevents
osteoblastic differentiation of chondrocytes by lowering beta-catenin
(CTNNB1) signaling
- reference_id: file:human/SOX9/SOX9-goa.tsv
supporting_text: GO:0000122 negative regulation of transcription by RNA
polymerase II biological_process ECO:0000314 IDA PMID:29503843
- term:
id: GO:0000978
label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: |
SOX9 binds to enhancer and promoter regions with sequence specificity. Deep
research describes binding to AACAAT-centered motifs in enhancers and super-enhancers.
action: ACCEPT
reason: |
This is a core molecular function. SOX9 recognizes specific DNA sequences via its
HMG-box domain and binds to cis-regulatory regions to activate transcription.
Well-supported by experimental evidence.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: Specifically binds the 5'-ACAAAG-3' DNA motif present in
enhancers and super-enhancers
- reference_id: file:human/SOX9/SOX9-goa.tsv
supporting_text: GO:0000978 RNA polymerase II cis-regulatory region
sequence-specific DNA binding molecular_function ECO:0000314 IDA
PMID:22110751
- term:
id: GO:0002062
label: chondrocyte differentiation
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: |
SOX9 is the master regulator of chondrocyte differentiation. Deep research and
UniProt extensively document this role with multiple IDA/IMP evidence codes.
action: ACCEPT
reason: |
This is arguably THE core biological process for SOX9. It is absolutely required
for chondrogenesis and is the most well-characterized function of SOX9. Extensively
validated experimentally.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: SOX9 is a human SOXE-family transcription factor
essential for lineage specification... orchestrate chondrogenesis
- reference_id: file:human/SOX9/SOX9-uniprot.txt
supporting_text: Transcription factor that plays a key role in
chondrocytes differentiation and skeletal development
- term:
id: GO:0032332
label: positive regulation of chondrocyte differentiation
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: |
SOX9 promotes chondrocyte differentiation with multiple IDA/IMP evidence codes
(PMID:21401405, PMID:20676705). This is a more specific term capturing SOX9's
role as a positive regulator.
action: ACCEPT
reason: |
This is core function. SOX9 positively drives chondrocyte differentiation through
direct transcriptional activation of cartilage genes and is required for multiple
stages of chondrogenesis.
supported_by:
- reference_id: file:human/SOX9/SOX9-goa.tsv
supporting_text: GO:0032332 positive regulation of chondrocyte
differentiation biological_process ECO:0000314 IDA PMID:21401405
- term:
id: GO:0048709
label: oligodendrocyte differentiation
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: |
SOX9 promotes oligodendrocyte differentiation and glial fate specification. This
is a critical function in neural development where SOX9 promotes glial over
neuronal fates.
action: ACCEPT
reason: |
This is a CORE function for the NEURON_DEVELOPMENT project context. SOX9 is
essential for oligodendrocyte lineage specification and is the glial counterpart
to proneural factors. This is NOT a peripheral function but rather one of SOX9's
two major core roles (cartilage AND glia).
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: GLIOGENESIS/OLIGODENDROCYTE DIFFERENTIATION - important
for glial fate specification
- term:
id: GO:0003677
label: DNA binding
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: |
SOX9 binds DNA via its HMG-box domain. This is a well-established molecular
function but is somewhat generic compared to the sequence-specific binding terms.
action: ACCEPT
reason: |
DNA binding is a fundamental molecular function of SOX9. While more specific terms
exist (sequence-specific binding), this parent term is also accurate and appropriate.
supported_by:
- reference_id: file:human/SOX9/SOX9-uniprot.txt
supporting_text: DNA_BIND 105..173 /note='HMG box'
- term:
id: GO:0005634
label: nucleus
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: Duplicate of earlier nucleus annotation. Same evidence and
conclusion.
action: ACCEPT
reason: Duplicate annotation with IEA evidence. Nuclear localization is
well-established.
supported_by:
- reference_id: file:human/SOX9/SOX9-uniprot.txt
supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
id: GO:0030154
label: cell differentiation
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: |
SOX9 is involved in differentiation of multiple cell types including chondrocytes,
glia, Sertoli cells, and various epithelial cells. This is a very broad parent term.
action: ACCEPT
reason: |
While generic, this term is accurate. SOX9 drives differentiation programs in
multiple lineages. More specific child terms are preferred but this parent term
is not incorrect.
supported_by:
- reference_id: file:human/SOX9/SOX9-uniprot.txt
supporting_text: Also acts as a regulator of proliferation and
differentiation in epithelial stem/progenitor cells
- term:
id: GO:0045893
label: positive regulation of DNA-templated transcription
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: |
SOX9 activates transcription as documented extensively. This is a parent term
less specific than the RNA Pol II terms but still accurate.
action: ACCEPT
reason: |
This broad term accurately captures SOX9's transactivation function. More specific
RNA Pol II terms are preferred but this is not incorrect.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: recruits co-activators CBP/p300 and TIP60... promotes
expression of genes important for chondrogenesis
- term:
id: GO:1990837
label: sequence-specific double-stranded DNA binding
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: |
SOX9 binds double-stranded DNA at specific sequences via its HMG-box domain.
IDA evidence exists (PMID:28473536).
action: ACCEPT
reason: |
This accurately describes SOX9's DNA-binding mode. The HMG-box recognizes specific
sequences in double-stranded DNA and bends it.
supported_by:
- reference_id: file:human/SOX9/SOX9-goa.tsv
supporting_text: GO:1990837 sequence-specific double-stranded DNA binding
molecular_function ECO:0000314 IDA PMID:28473536
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:12810722
review:
summary: |
Generic protein binding term from IPI evidence. SOX9 interacts with many partners
including SOX5/6, CBP/p300, beta-catenin, but this term lacks specificity.
action: REMOVE
reason: |
Per guidelines, avoid generic "protein binding" annotations as they don't convey
informative molecular function. More specific binding terms (e.g., transcription
co-activator binding) would be better if available.
supported_by:
- reference_id: PMID:12810722
supporting_text: 2003 Jun 16. A SOX9 defect of calmodulin-dependent
nuclear import in campomelic dysplasia/autosomal sex reversal.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21346191
review:
summary: Duplicate generic protein binding annotation from different
reference.
action: REMOVE
reason: |
Same rationale as previous protein binding annotation. Generic and uninformative
for molecular function.
supported_by:
- reference_id: PMID:21346191
supporting_text: 2011 Feb 23. Arid5a cooperates with Sox9 to stimulate
chondrocyte-specific transcription.
- term:
id: GO:0000976
label: transcription cis-regulatory region binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: |
SOX9 binds to enhancers and promoters. This is a parent term to the more specific
RNA Pol II cis-regulatory region binding.
action: ACCEPT
reason: |
Accurate term capturing SOX9's binding to regulatory regions. More specific child
terms exist but this is appropriate.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: binds the DNA minor groove... engages enhancer
architectures
- term:
id: GO:0000978
label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Duplicate of earlier IBA annotation for same term. Same evidence
supports.
action: ACCEPT
reason: Duplicate but accurate annotation of core molecular function.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: Specifically binds the 5'-ACAAAG-3' DNA motif present in
enhancers and super-enhancers
- term:
id: GO:0000981
label: DNA-binding transcription factor activity, RNA polymerase II-specific
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Duplicate of first IBA annotation. Multiple evidence codes support.
action: ACCEPT
reason: Core molecular function, well-supported.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: SOX9 is a human SOXE-family transcription factor
- term:
id: GO:0000987
label: cis-regulatory region sequence-specific DNA binding
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: |
Another term for sequence-specific binding to regulatory regions. Slight variation
in term hierarchy from GO:0000978.
action: ACCEPT
reason: |
Accurate molecular function term. While overlapping with other DNA-binding terms,
this captures the regulatory region specificity.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: binds AACAAT-centered motifs via its HMG-box
- term:
id: GO:0001228
label: DNA-binding transcription activator activity, RNA polymerase
II-specific
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: |
SOX9 has transcriptional activator activity with documented transactivation
domains (TAM and TAC). Multiple IDA evidence codes exist.
action: ACCEPT
reason: |
Core molecular function. SOX9 is primarily a transcriptional activator, though
it can also repress. Activator function is well-documented.
supported_by:
- reference_id: file:human/SOX9/SOX9-uniprot.txt
supporting_text: The transactivation domains TAM and TAC (for
transactivation domain in the middle and at the C-terminus,
respectively)
- reference_id: file:human/SOX9/SOX9-goa.tsv
supporting_text: GO:0001228 DNA-binding transcription activator activity,
RNA polymerase II-specific molecular_function ECO:0000314 IDA
PMID:21367821
- term:
id: GO:0001503
label: ossification
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: |
SOX9 is involved in skeletal development and endochondral ossification, where it
regulates the cartilage template that is replaced by bone.
action: KEEP_AS_NON_CORE
reason: |
While SOX9 affects ossification (primarily by regulating the cartilage template
for endochondral bone formation), this is a consequence of its chondrogenic
function rather than a distinct core role. The core function is chondrogenesis.
supported_by:
- reference_id: file:human/SOX9/SOX9-uniprot.txt
supporting_text: maintains chondrocyte columnar proliferation, delays
prehypertrophy and then prevents osteoblastic differentiation
- term:
id: GO:0001658
label: branching involved in ureteric bud morphogenesis
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: SOX9 regulates kidney development including ureteric bud branching.
action: KEEP_AS_NON_CORE
reason: |
Kidney development is a peripheral developmental role, not part of the core
cartilage/glial functions. Pleiotropic effect.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: Controls epithelial branching during kidney development
- term:
id: GO:0001894
label: tissue homeostasis
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: |
SOX9 plays roles in maintaining tissue homeostasis in intestinal epithelium and
other tissues.
action: KEEP_AS_NON_CORE
reason: |
Tissue homeostasis represents peripheral maintenance functions rather than core
transcription factor activities in cartilage and glial development.
supported_by:
- reference_id: file:human/SOX9/SOX9-goa.tsv
supporting_text: GO:0060729 intestinal epithelial structure maintenance
biological_process
- term:
id: GO:0002062
label: chondrocyte differentiation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Duplicate of earlier IBA annotation for chondrocyte
differentiation.
action: ACCEPT
reason: Core function, multiple evidence codes support.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: master regulator of chondrocyte differentiation
- term:
id: GO:0002683
label: negative regulation of immune system process
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: |
SOX9 may have immunomodulatory effects in certain contexts, but this is not
well-documented as a primary function.
action: KEEP_AS_NON_CORE
reason: |
Immune regulation is a peripheral effect, not related to core chondrogenic or
gliogenic functions. Likely context-dependent pleiotropic effect.
- term:
id: GO:0003170
label: heart valve development
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: SOX9 is involved in heart valve development with experimental
evidence.
action: KEEP_AS_NON_CORE
reason: Heart valve development is peripheral to core functions.
supported_by:
- reference_id: file:human/SOX9/SOX9-goa.tsv
supporting_text: GO:0003180 aortic valve morphogenesis biological_process
ECO:0000314 IDA PMID:22110751
- term:
id: GO:0003415
label: chondrocyte hypertrophy
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: |
SOX9 regulates chondrocyte hypertrophy. UniProt notes SOX9 is required for
chondrocyte hypertrophy both indirectly and directly.
action: ACCEPT
reason: |
Chondrocyte hypertrophy is part of SOX9's core chondrogenic program. This is a
specific stage of chondrocyte maturation that SOX9 controls.
supported_by:
- reference_id: file:human/SOX9/SOX9-uniprot.txt
supporting_text: Also required for chondrocyte hypertrophy, both
indirectly, by keeping the lineage fate of chondrocytes, and directly,
by remaining present in upper hypertrophic cells
- term:
id: GO:0003430
label: growth plate cartilage chondrocyte growth
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: |
SOX9 maintains chondrocyte proliferation in growth plate cartilage as part of
its chondrogenic program.
action: ACCEPT
reason: |
Growth plate chondrocyte regulation is part of SOX9's core chondrogenic function.
This represents a specific developmental stage in cartilage biology.
supported_by:
- reference_id: file:human/SOX9/SOX9-uniprot.txt
supporting_text: maintains chondrocyte columnar proliferation
- term:
id: GO:0003700
label: DNA-binding transcription factor activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: |
General parent term for transcription factor activity. Less specific than RNA
Pol II-specific terms.
action: ACCEPT
reason: |
Accurate but broad molecular function term. More specific child terms are preferred
but this is not incorrect.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: SOX9 is a human SOXE-family transcription factor
- term:
id: GO:0005667
label: transcription regulator complex
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: |
SOX9 forms complexes with partner proteins including SOX5/6, CBP/p300. It can
also homodimerize.
action: ACCEPT
reason: |
SOX9 functions as part of transcriptional regulatory complexes, cooperating with
SOX5/6 on paired SOX sites and recruiting coactivators. This is accurate.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: frequently in cooperation with SOX5/6 on paired SOX sites
- reference_id: file:human/SOX9/SOX9-uniprot.txt
supporting_text: Homodimer; homodimerization is required for activity
- term:
id: GO:0007165
label: signal transduction
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: |
Extremely broad term. SOX9 responds to and mediates signaling pathways like BMP,
TGF-beta, but this term is too generic.
action: MARK_AS_OVER_ANNOTATED
reason: |
This term is overly broad and uninformative. SOX9 participates in specific
signaling contexts but "signal transduction" as a general term doesn't capture
its function meaningfully.
- term:
id: GO:0007173
label: epidermal growth factor receptor signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: |
SOX9 is involved in EGFR signaling in urothelial and other epithelial contexts.
Deep research mentions EGFR-ERK-SOX9 cascade.
action: KEEP_AS_NON_CORE
reason: |
EGFR pathway involvement is context-specific (urothelium, epithelial regeneration)
and peripheral to core functions. Not part of cartilage/glial programs.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: An EGFR-ERK-SOX9 signaling cascade links urothelial
development and regeneration to cancer
- term:
id: GO:0007417
label: central nervous system development
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: |
SOX9 promotes glial fate specification and oligodendrocyte differentiation in
the CNS. This is one of its core functions.
action: ACCEPT
reason: |
CNS development via gliogenesis is a CORE function of SOX9 in the NEURON_DEVELOPMENT
project context. SOX9 promotes glial over neuronal fates.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: GLIOGENESIS/OLIGODENDROCYTE DIFFERENTIATION - important
for glial fate specification
- term:
id: GO:0008013
label: beta-catenin binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: |
SOX9 interacts with beta-catenin to antagonize Wnt signaling in chondrocytes.
This is a specific and informative binding term.
action: ACCEPT
reason: |
Beta-catenin binding is a specific molecular function relevant to SOX9's mechanism
of action. Unlike generic "protein binding," this term conveys functional information
about SOX9's antagonism of Wnt signaling.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: Antagonizes β-catenin in chondrocytes
- reference_id: file:human/SOX9/SOX9-uniprot.txt
supporting_text: Interacts with beta-catenin (CTNNB1); inhibiting CTNNB1
activity by competing with the binding sites of TCF/LEF within CTNNB1
- term:
id: GO:0010467
label: gene expression
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Extremely generic term for any gene expression regulation.
action: MARK_AS_OVER_ANNOTATED
reason: |
Too broad to be informative. More specific terms about transcriptional regulation
better capture SOX9's function.
- term:
id: GO:0010628
label: positive regulation of gene expression
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: |
Slightly more specific than gene expression but still quite broad. Has IDA
evidence (PMID:24681825).
action: ACCEPT
reason: |
While broad, this accurately captures SOX9's role as a transcriptional activator.
More specific terms are preferred but this is acceptable.
supported_by:
- reference_id: file:human/SOX9/SOX9-goa.tsv
supporting_text: GO:0010628 positive regulation of gene expression
biological_process ECO:0000314 IDA PMID:24681825
- term:
id: GO:0030279
label: negative regulation of ossification
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: |
SOX9 delays ossification by maintaining cartilage and preventing premature
osteoblast differentiation. Has IDA evidence (PMID:29503843).
action: ACCEPT
reason: |
This is part of SOX9's core chondrogenic program. SOX9 blocks osteoblast
differentiation to maintain chondrocyte identity, which delays ossification.
supported_by:
- reference_id: file:human/SOX9/SOX9-uniprot.txt
supporting_text: prevents osteoblastic differentiation of chondrocytes by
lowering beta-catenin (CTNNB1) signaling
- reference_id: file:human/SOX9/SOX9-goa.tsv
supporting_text: GO:0030279 negative regulation of ossification
biological_process ECO:0000314 IDA PMID:29503843
- term:
id: GO:0030850
label: prostate gland development
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: SOX9 is expressed in prostate development with IEP evidence.
action: KEEP_AS_NON_CORE
reason: |
Prostate development is a peripheral epithelial developmental role, not core
cartilage/glial function.
supported_by:
- reference_id: file:human/SOX9/SOX9-goa.tsv
supporting_text: GO:0030850 prostate gland development biological_process
ECO:0000270 IEP PMID:20103652
- term:
id: GO:0030879
label: mammary gland development
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: SOX9 plays roles in mammary gland epithelial development.
action: KEEP_AS_NON_CORE
reason: Peripheral epithelial developmental function.
- term:
id: GO:0030903
label: notochord development
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: SOX9 is involved in notochord development.
action: KEEP_AS_NON_CORE
reason: |
Notochord development is a developmental process but peripheral to core cartilage/glial
functions.
- term:
id: GO:0032332
label: positive regulation of chondrocyte differentiation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Duplicate of earlier IBA annotation for same term.
action: ACCEPT
reason: Core function with multiple evidence codes.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: master regulator of chondrocyte differentiation
- term:
id: GO:0043425
label: bHLH transcription factor binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: |
SOX9 may interact with bHLH transcription factors in certain contexts, but this
is not well-documented as a major interaction.
action: UNDECIDED
reason: |
Unclear if this represents a significant molecular function for SOX9. Would need
to review evidence for specific bHLH factor interactions relevant to SOX9's core
functions.
- term:
id: GO:0043565
label: sequence-specific DNA binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: |
SOX9 binds DNA in sequence-specific manner via AACAAT motif recognition. Has
IDA evidence (PMID:31194875).
action: ACCEPT
reason: Core molecular function, well-supported.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: binds AACAAT-centered motifs via its HMG-box
- reference_id: file:human/SOX9/SOX9-goa.tsv
supporting_text: GO:0043565 sequence-specific DNA binding
molecular_function ECO:0000314 IDA PMID:31194875
- term:
id: GO:0045668
label: negative regulation of osteoblast differentiation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: |
SOX9 blocks osteoblast differentiation to maintain chondrocyte identity. Has
ISS evidence.
action: ACCEPT
reason: |
This is part of SOX9's core mechanism for maintaining chondrocyte fate. SOX9
antagonizes osteoblast genes and beta-catenin to prevent osteogenesis.
supported_by:
- reference_id: file:human/SOX9/SOX9-uniprot.txt
supporting_text: prevents osteoblastic differentiation of chondrocytes
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: |
SOX9 activates RNA Pol II transcription with multiple IDA/IMP evidence codes.
action: ACCEPT
reason: Core transcriptional activator function, well-supported.
supported_by:
- reference_id: file:human/SOX9/SOX9-goa.tsv
supporting_text: GO:0045944 positive regulation of transcription by RNA
polymerase II biological_process ECO:0000314 IDA PMID:22110751
- term:
id: GO:0046322
label: negative regulation of fatty acid oxidation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: |
Deep research mentions low lipid levels promote SOX9 expression and chondrogenic
commitment, with SOX9 suppressing fatty acid oxidation.
action: KEEP_AS_NON_CORE
reason: |
While documented, this represents a metabolic coupling to chondrogenic commitment
rather than a core transcription factor function. Peripheral metabolic effect.
supported_by:
- reference_id: file:human/SOX9/SOX9-uniprot.txt
supporting_text: when lipids levels are low, FOXO (FOXO1 and FOXO3)
transcription factors promote expression of SOX9, which induces
chondrogenic commitment and suppresses fatty acid oxidation
- term:
id: GO:0051216
label: cartilage development
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: |
Broad parent term for cartilage development. SOX9 is the master regulator of
cartilage development.
action: ACCEPT
reason: |
This is a core biological process for SOX9. While less specific than chondrocyte
differentiation, it accurately captures SOX9's role in cartilage biology.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: orchestrate chondrogenesis
- term:
id: GO:0060009
label: Sertoli cell development
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: SOX9 is critical for Sertoli cell development and sex
determination.
action: KEEP_AS_NON_CORE
reason: |
Sex determination and Sertoli cell development are important biological functions
of SOX9 but peripheral to the core cartilage/glial roles.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: Sex determination (testis development, Sertoli cell
differentiation)
- term:
id: GO:0060174
label: limb bud formation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: SOX9 is involved in limb skeletal development.
action: KEEP_AS_NON_CORE
reason: |
Limb development involves SOX9's chondrogenic function but this specific term
represents a developmental context rather than core molecular function.
- term:
id: GO:0070168
label: negative regulation of biomineral tissue development
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: |
SOX9 inhibits bone mineralization, maintaining cartilage. Has IDA evidence
(PMID:22110751).
action: ACCEPT
reason: |
This is part of SOX9's mechanism for maintaining cartilage identity by preventing
premature mineralization and osteoblast differentiation.
supported_by:
- reference_id: file:human/SOX9/SOX9-goa.tsv
supporting_text: GO:0070168 negative regulation of biomineral tissue
development biological_process ECO:0000314 IDA PMID:22110751
- term:
id: GO:0070371
label: ERK1 and ERK2 cascade
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: SOX9 is involved in ERK signaling cascades in epithelial contexts.
action: KEEP_AS_NON_CORE
reason: |
ERK cascade involvement is context-specific (EGFR-ERK-SOX9 in urothelium) and
peripheral to core functions.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: An EGFR-ERK-SOX9 signaling cascade
- term:
id: GO:0070542
label: response to fatty acid
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Related to the lipid/fatty acid oxidation effects noted earlier.
action: KEEP_AS_NON_CORE
reason: Peripheral metabolic response, not core transcription factor
function.
- term:
id: GO:0071260
label: cellular response to mechanical stimulus
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: SOX9 may respond to mechanical stimuli in cartilage contexts.
action: KEEP_AS_NON_CORE
reason: |
While potentially relevant to cartilage biology, this is a contextual response
rather than core molecular function.
- term:
id: GO:0071364
label: cellular response to epidermal growth factor stimulus
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Related to EGFR signaling pathway involvement noted earlier.
action: KEEP_AS_NON_CORE
reason: Context-specific response in epithelial tissues, not core function.
- term:
id: GO:0071504
label: cellular response to heparin
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: SOX9 may respond to heparin in certain contexts.
action: KEEP_AS_NON_CORE
reason: Highly specific contextual response, unclear relevance to core
functions.
- term:
id: GO:0071560
label: cellular response to transforming growth factor beta stimulus
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: |
SOX9 responds to TGF-beta signaling which regulates chondrogenesis. Has IDA
evidence (PMID:21401405).
action: ACCEPT
reason: |
TGF-beta signaling is central to chondrogenesis regulation. SOX9's response to
TGF-beta is part of its core chondrogenic program.
supported_by:
- reference_id: file:human/SOX9/SOX9-goa.tsv
supporting_text: GO:0071560 cellular response to transforming growth
factor beta stimulus biological_process ECO:0000314 IDA PMID:21401405
- term:
id: GO:0071599
label: otic vesicle development
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: SOX9 is involved in inner ear development.
action: KEEP_AS_NON_CORE
reason: Peripheral developmental process in sensory organ development.
- term:
id: GO:0072034
label: renal vesicle induction
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: SOX9 regulates kidney development including renal vesicle
formation.
action: KEEP_AS_NON_CORE
reason: Peripheral kidney development function.
- term:
id: GO:0072170
label: metanephric tubule development
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: SOX9 involved in kidney tubule development.
action: KEEP_AS_NON_CORE
reason: Peripheral kidney development function.
- term:
id: GO:0072190
label: ureter urothelium development
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: SOX9 regulates urothelial development.
action: KEEP_AS_NON_CORE
reason: Peripheral epithelial development.
- term:
id: GO:0090184
label: positive regulation of kidney development
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: SOX9 promotes kidney development.
action: KEEP_AS_NON_CORE
reason: Peripheral developmental function.
- term:
id: GO:0090190
label: positive regulation of branching involved in ureteric bud
morphogenesis
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: More specific kidney branching term.
action: KEEP_AS_NON_CORE
reason: Peripheral kidney development function.
- term:
id: GO:0097157
label: pre-mRNA intronic binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: |
Deep research notes SOX9 regulates alternative splicing in beta cells, which may
involve intronic binding.
action: UNDECIDED
reason: |
This is an interesting molecular function related to the alternative splicing
role discovered in beta cells, but unclear if this is broadly relevant to SOX9's
core functions.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: SOX9 persists in mature β cells and regulates alternative
splicing programs
- term:
id: GO:1904864
label: negative regulation of beta-catenin-TCF complex assembly
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: |
SOX9 antagonizes beta-catenin by competing for binding sites with TCF/LEF factors.
action: ACCEPT
reason: |
This is a specific molecular mechanism by which SOX9 antagonizes Wnt signaling
to maintain chondrocyte identity. Part of core chondrogenic function.
supported_by:
- reference_id: file:human/SOX9/SOX9-uniprot.txt
supporting_text: Interacts with beta-catenin (CTNNB1); inhibiting CTNNB1
activity by competing with the binding sites of TCF/LEF within CTNNB1
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: IDA
original_reference_id: GO_REF:0000052
review:
summary: SOX9 localizes to nucleoplasm as a nuclear transcription factor.
action: ACCEPT
reason: |
Nucleoplasm is the appropriate sub-nuclear compartment for transcription factors.
More specific than just "nucleus."
supported_by:
- reference_id: file:human/SOX9/SOX9-goa.tsv
supporting_text: GO:0005654 nucleoplasm cellular_component ECO:0000314 IDA
GO_REF:0000052
- term:
id: GO:0000122
label: negative regulation of transcription by RNA polymerase II
evidence_type: IMP
original_reference_id: PMID:24014021
review:
summary: Duplicate of earlier IBA annotation with additional IMP evidence.
action: ACCEPT
reason: SOX9 has documented repressive functions. Multiple evidence codes
support.
supported_by:
- reference_id: file:human/SOX9/SOX9-goa.tsv
supporting_text: GO:0000122 negative regulation of transcription by RNA
polymerase II biological_process ECO:0000315 IMP PMID:24014021
- reference_id: PMID:24014021
supporting_text: 2013 Sep 6. miR-1247 functions by targeting cartilage
transcription factor SOX9.
- term:
id: GO:0001228
label: DNA-binding transcription activator activity, RNA polymerase
II-specific
evidence_type: IDA
original_reference_id: PMID:21367821
review:
summary: Duplicate with IDA evidence from different publication.
action: ACCEPT
reason: Core molecular function with strong experimental support.
supported_by:
- reference_id: PMID:21367821
supporting_text: Sox9 sustains chondrocyte survival and hypertrophy in
part through Pik3ca-Akt pathways.
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IMP
original_reference_id: PMID:21367821
review:
summary: Duplicate with IMP evidence.
action: ACCEPT
reason: Core function with experimental evidence.
supported_by:
- reference_id: PMID:21367821
supporting_text: Sox9 sustains chondrocyte survival and hypertrophy in
part through Pik3ca-Akt pathways.
- term:
id: GO:0000978
label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
evidence_type: IDA
original_reference_id: PMID:22110751
review:
summary: Duplicate with IDA evidence from heart valve study.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:22110751
supporting_text: Inhibitory role of Notch1 in calcific aortic valve
disease.
- term:
id: GO:0001228
label: DNA-binding transcription activator activity, RNA polymerase
II-specific
evidence_type: IDA
original_reference_id: PMID:22110751
review:
summary: Another duplicate with IDA evidence.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:22110751
supporting_text: Inhibitory role of Notch1 in calcific aortic valve
disease.
- term:
id: GO:0003180
label: aortic valve morphogenesis
evidence_type: IDA
original_reference_id: PMID:22110751
review:
summary: Specific heart valve development term with experimental evidence.
action: KEEP_AS_NON_CORE
reason: Heart valve morphogenesis is peripheral to core cartilage/glial
functions.
supported_by:
- reference_id: file:human/SOX9/SOX9-goa.tsv
supporting_text: GO:0003180 aortic valve morphogenesis biological_process
ECO:0000314 IDA PMID:22110751
- reference_id: PMID:22110751
supporting_text: Inhibitory role of Notch1 in calcific aortic valve
disease.
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:22110751
review:
summary: Another duplicate from heart valve study.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:22110751
supporting_text: Inhibitory role of Notch1 in calcific aortic valve
disease.
- term:
id: GO:0070168
label: negative regulation of biomineral tissue development
evidence_type: IDA
original_reference_id: PMID:22110751
review:
summary: Duplicate of earlier annotation with IDA evidence from heart valve
study.
action: ACCEPT
reason: Part of core mechanism for maintaining cartilage over bone.
supported_by:
- reference_id: PMID:22110751
supporting_text: Inhibitory role of Notch1 in calcific aortic valve
disease.
- term:
id: GO:0000981
label: DNA-binding transcription factor activity, RNA polymerase II-specific
evidence_type: IDA
original_reference_id: PMID:20484372
review:
summary: Multiple IDA evidence codes from different publications.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:20484372
supporting_text: May 19. The dimerization domain of SOX9 is required for
transcription activation of a chondrocyte-specific chromatin DNA
template.
- term:
id: GO:0000981
label: DNA-binding transcription factor activity, RNA polymerase II-specific
evidence_type: IDA
original_reference_id: PMID:21412441
review:
summary: Another IDA evidence from sex determination study.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:21412441
supporting_text: Failure of SOX9 regulation in 46XY disorders of sex
development with SRY, SOX9 and SF1 mutations.
- term:
id: GO:0001228
label: DNA-binding transcription activator activity, RNA polymerase
II-specific
evidence_type: IDA
original_reference_id: PMID:20484372
review:
summary: Duplicate IDA evidence.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:20484372
supporting_text: May 19. The dimerization domain of SOX9 is required for
transcription activation of a chondrocyte-specific chromatin DNA
template.
- term:
id: GO:0001228
label: DNA-binding transcription activator activity, RNA polymerase
II-specific
evidence_type: IDA
original_reference_id: PMID:20530484
review:
summary: Another IDA evidence.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:20530484
supporting_text: Epub 2010 Jun 8. SOX9, through interaction with
microphthalmia-associated transcription factor (MITF) and OTX2,
regulates BEST1 expression in the retinal pigment epithelium.
- term:
id: GO:1902894
label: negative regulation of miRNA transcription
evidence_type: IDA
original_reference_id: PMID:26687115
review:
summary: SOX9 regulates miRNA expression in cartilage contexts.
action: KEEP_AS_NON_CORE
reason: |
While experimentally validated, miRNA regulation is a secondary regulatory
mechanism rather than core transcription factor function.
supported_by:
- reference_id: file:human/SOX9/SOX9-goa.tsv
supporting_text: GO:1902894 negative regulation of miRNA transcription
biological_process ECO:0000314 IDA PMID:26687115
- reference_id: PMID:26687115
supporting_text: 2015 Dec 19. The microRNA-29 family in cartilage
homeostasis and osteoarthritis.
- term:
id: GO:1990837
label: sequence-specific double-stranded DNA binding
evidence_type: IDA
original_reference_id: PMID:28473536
review:
summary: Duplicate of earlier IEA annotation with IDA evidence.
action: ACCEPT
reason: Core molecular function with experimental support.
supported_by:
- reference_id: PMID:28473536
supporting_text: Impact of cytosine methylation on DNA binding
specificities of human transcription factors.
- term:
id: GO:0001228
label: DNA-binding transcription activator activity, RNA polymerase
II-specific
evidence_type: IDA
original_reference_id: PMID:31194875
review:
summary: More IDA evidence from transactivation domain study.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:31194875
supporting_text: The SOXE transcription factors-SOX8, SOX9 and SOX10-share
a bi-partite transactivation mechanism.
- term:
id: GO:0043565
label: sequence-specific DNA binding
evidence_type: IDA
original_reference_id: PMID:31194875
review:
summary: Duplicate with IDA evidence.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:31194875
supporting_text: The SOXE transcription factors-SOX8, SOX9 and SOX10-share
a bi-partite transactivation mechanism.
- term:
id: GO:0002062
label: chondrocyte differentiation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Multiple evidence codes for this core function.
action: ACCEPT
reason: Core function with ISS evidence.
- term:
id: GO:0003430
label: growth plate cartilage chondrocyte growth
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate with ISS evidence.
action: ACCEPT
reason: Part of core chondrogenic program.
- term:
id: GO:0045668
label: negative regulation of osteoblast differentiation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate with ISS evidence.
action: ACCEPT
reason: Core mechanism for maintaining chondrocyte identity.
- term:
id: GO:0046322
label: negative regulation of fatty acid oxidation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate with ISS evidence.
action: KEEP_AS_NON_CORE
reason: Peripheral metabolic effect.
- term:
id: GO:0070542
label: response to fatty acid
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate with ISS evidence.
action: KEEP_AS_NON_CORE
reason: Peripheral metabolic response.
- term:
id: GO:0000785
label: chromatin
evidence_type: ISA
original_reference_id: GO_REF:0000113
review:
summary: |
SOX9 binds chromatin as a transcription factor. Deep research notes it can act
as a pioneer factor at super-enhancers.
action: ACCEPT
reason: |
Chromatin localization is appropriate for a transcription factor that engages
enhancers and promoters.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: Can act as a pioneer factor at super-enhancers
- term:
id: GO:0000981
label: DNA-binding transcription factor activity, RNA polymerase II-specific
evidence_type: ISA
original_reference_id: GO_REF:0000113
review:
summary: ISA evidence from TFClass database.
action: ACCEPT
reason: Core molecular function supported by database annotation.
- term:
id: GO:0010628
label: positive regulation of gene expression
evidence_type: IDA
original_reference_id: PMID:24681825
review:
summary: Duplicate with IDA evidence.
action: ACCEPT
reason: Core transcriptional activator function.
supported_by:
- reference_id: PMID:24681825
supporting_text: The NLR-related protein NWD1 is associated with prostate
cancer and modulates androgen receptor signaling.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:28263186
review:
summary: Another generic protein binding annotation (DDRGK1 interaction).
action: REMOVE
reason: |
Generic protein binding term. While DDRGK1 interaction affects SOX9 ubiquitination,
the generic term doesn't convey functional information.
supported_by:
- reference_id: PMID:28263186
supporting_text: Mar 6. Loss of DDRGK1 modulates SOX9 ubiquitination in
spondyloepimetaphyseal dysplasia.
- term:
id: GO:0005634
label: nucleus
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Multiple evidence codes for nuclear localization.
action: ACCEPT
reason: Well-established cellular component.
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:26634652
review:
summary: IDA evidence for nuclear localization.
action: ACCEPT
reason: Well-established with experimental evidence.
supported_by:
- reference_id: PMID:26634652
supporting_text: Valve Endothelial Cell-Derived Tgfβ1 Signaling Promotes
Nuclear Localization of Sox9 in Interstitial Cells Associated With
Attenuated Calcification.
- term:
id: GO:0000978
label: RNA polymerase II cis-regulatory region sequence-specific DNA binding
evidence_type: IDA
original_reference_id: PMID:20530484
review:
summary: Another IDA evidence.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:20530484
supporting_text: Epub 2010 Jun 8. SOX9, through interaction with
microphthalmia-associated transcription factor (MITF) and OTX2,
regulates BEST1 expression in the retinal pigment epithelium.
- term:
id: GO:0061036
label: positive regulation of cartilage development
evidence_type: IDA
original_reference_id: PMID:29503843
review:
summary: SOX9 promotes cartilage development with IDA evidence.
action: ACCEPT
reason: |
This is essentially a parent term encompassing SOX9's chondrogenic functions.
Core function.
supported_by:
- reference_id: file:human/SOX9/SOX9-goa.tsv
supporting_text: GO:0061036 positive regulation of cartilage development
biological_process ECO:0000314 IDA PMID:29503843
- reference_id: PMID:29503843
supporting_text: Nov 2. Sox9 augments BMP2-induced chondrogenic
differentiation by downregulating Smad7 in mesenchymal stem cells
(MSCs).
- term:
id: GO:1902732
label: positive regulation of chondrocyte proliferation
evidence_type: IDA
original_reference_id: PMID:29503843
review:
summary: SOX9 promotes chondrocyte proliferation in growth plate.
action: ACCEPT
reason: Part of core chondrogenic program maintaining columnar
proliferation.
supported_by:
- reference_id: file:human/SOX9/SOX9-uniprot.txt
supporting_text: maintains chondrocyte columnar proliferation
- reference_id: PMID:29503843
supporting_text: Nov 2. Sox9 augments BMP2-induced chondrogenic
differentiation by downregulating Smad7 in mesenchymal stem cells
(MSCs).
- term:
id: GO:0030279
label: negative regulation of ossification
evidence_type: IDA
original_reference_id: PMID:29503843
review:
summary: Duplicate with IDA evidence.
action: ACCEPT
reason: Part of core mechanism.
supported_by:
- reference_id: PMID:29503843
supporting_text: Nov 2. Sox9 augments BMP2-induced chondrogenic
differentiation by downregulating Smad7 in mesenchymal stem cells
(MSCs).
- term:
id: GO:0000122
label: negative regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:29503843
review:
summary: More IDA evidence for repressive function.
action: ACCEPT
reason: Documented repressive capability.
supported_by:
- reference_id: PMID:29503843
supporting_text: Nov 2. Sox9 augments BMP2-induced chondrogenic
differentiation by downregulating Smad7 in mesenchymal stem cells
(MSCs).
- term:
id: GO:0001502
label: cartilage condensation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: |
SOX9 is absolutely required for precartilaginous condensation, the first step
in chondrogenesis.
action: ACCEPT
reason: |
Cartilage condensation is the initial step in chondrogenesis where SOX9 is
absolutely required. This is core chondrogenic function.
supported_by:
- reference_id: file:human/SOX9/SOX9-uniprot.txt
supporting_text: Absolutely required for precartilaginous condensation,
the first step in chondrogenesis
- term:
id: GO:0014036
label: neural crest cell fate specification
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: SOX9 is involved in neural crest development.
action: KEEP_AS_NON_CORE
reason: |
Neural crest fate specification is peripheral to core cartilage/glial functions.
While SOX9 may affect neural crest, this is not its primary role.
- term:
id: GO:0071773
label: cellular response to BMP stimulus
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: SOX9 responds to BMP signaling which regulates chondrogenesis.
action: ACCEPT
reason: |
BMP signaling is central to chondrogenesis and SOX9 is a key effector of BMP
responses in cartilage differentiation.
supported_by:
- reference_id: file:human/SOX9/SOX9-uniprot.txt
supporting_text: Acts in cooperation with the Hedgehog pathway-dependent
GLI (GLI1 and GLI3) transcription factors
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5626938
review:
summary: Duplicate nucleoplasm annotation from Reactome.
action: ACCEPT
reason: Appropriate sub-nuclear compartment.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8985343
review:
summary: Another Reactome TAS annotation for nucleoplasm.
action: ACCEPT
reason: Appropriate sub-nuclear compartment.
- term:
id: GO:0032332
label: positive regulation of chondrocyte differentiation
evidence_type: IDA
original_reference_id: PMID:21401405
review:
summary: More IDA evidence for core function.
action: ACCEPT
reason: Core chondrogenic function.
supported_by:
- reference_id: PMID:21401405
supporting_text: Oct 21. Electroporation-mediated transfer of SOX trio
genes (SOX-5, SOX-6, and SOX-9) to enhance the chondrogenesis of
mesenchymal stem cells.
- term:
id: GO:0061036
label: positive regulation of cartilage development
evidence_type: IDA
original_reference_id: PMID:21401405
review:
summary: Duplicate with IDA evidence.
action: ACCEPT
reason: Core chondrogenic function.
supported_by:
- reference_id: PMID:21401405
supporting_text: Oct 21. Electroporation-mediated transfer of SOX trio
genes (SOX-5, SOX-6, and SOX-9) to enhance the chondrogenesis of
mesenchymal stem cells.
- term:
id: GO:0071560
label: cellular response to transforming growth factor beta stimulus
evidence_type: IDA
original_reference_id: PMID:21401405
review:
summary: Duplicate with IDA evidence.
action: ACCEPT
reason: Part of core chondrogenic signaling response.
supported_by:
- reference_id: PMID:21401405
supporting_text: Oct 21. Electroporation-mediated transfer of SOX trio
genes (SOX-5, SOX-6, and SOX-9) to enhance the chondrogenesis of
mesenchymal stem cells.
- term:
id: GO:0003415
label: chondrocyte hypertrophy
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate with ISS evidence.
action: ACCEPT
reason: Core chondrogenic program.
- term:
id: GO:0003682
label: chromatin binding
evidence_type: IDA
original_reference_id: PMID:20484372
review:
summary: SOX9 binds chromatin with IDA evidence.
action: ACCEPT
reason: |
Chromatin binding is a specific molecular function relevant to SOX9's role as a
transcription factor engaging chromatin.
supported_by:
- reference_id: file:human/SOX9/SOX9-goa.tsv
supporting_text: GO:0003682 chromatin binding molecular_function
ECO:0000314 IDA PMID:20484372
- reference_id: PMID:20484372
supporting_text: May 19. The dimerization domain of SOX9 is required for
transcription activation of a chondrocyte-specific chromatin DNA
template.
- term:
id: GO:0006334
label: nucleosome assembly
evidence_type: IDA
original_reference_id: PMID:20484372
review:
summary: |
PMID:20484372 shows SOX9 dimerization is required for nucleosome assembly during
chondrocyte-specific transcription activation.
action: KEEP_AS_NON_CORE
reason: |
While experimentally supported, nucleosome assembly is a chromatin remodeling
mechanism rather than a core transcription factor function. It's part of the
mechanistic process but peripheral to the primary role.
supported_by:
- reference_id: file:human/SOX9/SOX9-goa.tsv
supporting_text: GO:0006334 nucleosome assembly biological_process
ECO:0000314 IDA PMID:20484372
- reference_id: PMID:20484372
supporting_text: May 19. The dimerization domain of SOX9 is required for
transcription activation of a chondrocyte-specific chromatin DNA
template.
- term:
id: GO:0006338
label: chromatin remodeling
evidence_type: IDA
original_reference_id: PMID:20484372
review:
summary: SOX9 is involved in chromatin remodeling at target genes.
action: KEEP_AS_NON_CORE
reason: |
Chromatin remodeling is a mechanistic process supporting transcription activation
but not a core defining function of SOX9.
supported_by:
- reference_id: PMID:20484372
supporting_text: May 19. The dimerization domain of SOX9 is required for
transcription activation of a chondrocyte-specific chromatin DNA
template.
- term:
id: GO:0007173
label: epidermal growth factor receptor signaling pathway
evidence_type: ISS
original_reference_id: PMID:21512138
review:
summary: Duplicate with ISS evidence.
action: KEEP_AS_NON_CORE
reason: Context-specific signaling in epithelial tissues.
supported_by:
- reference_id: PMID:21512138
supporting_text: Epub 2011 Apr 21. An EGFR-ERK-SOX9 signaling cascade
links urothelial development and regeneration to cancer.
- term:
id: GO:0008284
label: positive regulation of cell population proliferation
evidence_type: IMP
original_reference_id: PMID:20651055
review:
summary: SOX9 promotes proliferation in certain contexts (lung
adenocarcinoma study).
action: KEEP_AS_NON_CORE
reason: |
While SOX9 does promote chondrocyte proliferation (core function), this generic
proliferation term from a cancer study represents peripheral effects rather than
the specific chondrocyte proliferation that is core.
supported_by:
- reference_id: PMID:20651055
supporting_text: Upregulation of SOX9 in lung adenocarcinoma and its
involvement in the regulation of cell growth and tumorigenicity.
- term:
id: GO:0010634
label: positive regulation of epithelial cell migration
evidence_type: IMP
original_reference_id: PMID:21512138
review:
summary: SOX9 promotes epithelial cell migration in urothelial contexts.
action: KEEP_AS_NON_CORE
reason: Context-specific epithelial function, not core cartilage/glial role.
supported_by:
- reference_id: PMID:21512138
supporting_text: Epub 2011 Apr 21. An EGFR-ERK-SOX9 signaling cascade
links urothelial development and regeneration to cancer.
- term:
id: GO:0045892
label: negative regulation of DNA-templated transcription
evidence_type: IMP
original_reference_id: PMID:20651055
review:
summary: General transcriptional repression term with IMP evidence.
action: ACCEPT
reason: |
SOX9 has documented repressive functions. More specific RNA Pol II term is
preferred but this is acceptable.
supported_by:
- reference_id: PMID:20651055
supporting_text: Upregulation of SOX9 in lung adenocarcinoma and its
involvement in the regulation of cell growth and tumorigenicity.
- term:
id: GO:0045893
label: positive regulation of DNA-templated transcription
evidence_type: IMP
original_reference_id: PMID:20651055
review:
summary: General transcriptional activation term with IMP evidence.
action: ACCEPT
reason: |
SOX9 is primarily a transcriptional activator. More specific RNA Pol II term is
preferred but this is acceptable.
supported_by:
- reference_id: PMID:20651055
supporting_text: Upregulation of SOX9 in lung adenocarcinoma and its
involvement in the regulation of cell growth and tumorigenicity.
- term:
id: GO:0070371
label: ERK1 and ERK2 cascade
evidence_type: ISS
original_reference_id: PMID:21512138
review:
summary: Duplicate ISS evidence.
action: KEEP_AS_NON_CORE
reason: Context-specific signaling.
supported_by:
- reference_id: PMID:21512138
supporting_text: Epub 2011 Apr 21. An EGFR-ERK-SOX9 signaling cascade
links urothelial development and regeneration to cancer.
- term:
id: GO:0071260
label: cellular response to mechanical stimulus
evidence_type: ISS
original_reference_id: PMID:21512138
review:
summary: Duplicate ISS evidence.
action: KEEP_AS_NON_CORE
reason: Context-specific response.
supported_by:
- reference_id: PMID:21512138
supporting_text: Epub 2011 Apr 21. An EGFR-ERK-SOX9 signaling cascade
links urothelial development and regeneration to cancer.
- term:
id: GO:0071364
label: cellular response to epidermal growth factor stimulus
evidence_type: ISS
original_reference_id: PMID:21512138
review:
summary: Duplicate ISS evidence.
action: KEEP_AS_NON_CORE
reason: Context-specific response.
supported_by:
- reference_id: PMID:21512138
supporting_text: Epub 2011 Apr 21. An EGFR-ERK-SOX9 signaling cascade
links urothelial development and regeneration to cancer.
- term:
id: GO:0071504
label: cellular response to heparin
evidence_type: ISS
original_reference_id: PMID:21512138
review:
summary: Duplicate ISS evidence.
action: KEEP_AS_NON_CORE
reason: Context-specific response.
supported_by:
- reference_id: PMID:21512138
supporting_text: Epub 2011 Apr 21. An EGFR-ERK-SOX9 signaling cascade
links urothelial development and regeneration to cancer.
- term:
id: GO:2000020
label: positive regulation of male gonad development
evidence_type: IDA
original_reference_id: PMID:21412441
review:
summary: SOX9 promotes testis development with IDA evidence.
action: KEEP_AS_NON_CORE
reason: |
Sex determination is an important SOX9 function but peripheral to core cartilage/glial
roles.
supported_by:
- reference_id: PMID:21412441
supporting_text: Failure of SOX9 regulation in 46XY disorders of sex
development with SRY, SOX9 and SF1 mutations.
- term:
id: GO:2000741
label: positive regulation of mesenchymal stem cell differentiation
evidence_type: IDA
original_reference_id: PMID:21401405
review:
summary: SOX9 promotes MSC differentiation toward chondrocytes.
action: ACCEPT
reason: |
MSC differentiation toward chondrocytes is part of the chondrogenic program.
This captures an earlier step in the lineage commitment.
supported_by:
- reference_id: PMID:21401405
supporting_text: Oct 21. Electroporation-mediated transfer of SOX trio
genes (SOX-5, SOX-6, and SOX-9) to enhance the chondrogenesis of
mesenchymal stem cells.
- term:
id: GO:0000987
label: cis-regulatory region sequence-specific DNA binding
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate with ISS evidence.
action: ACCEPT
reason: Core molecular function.
- term:
id: GO:0001502
label: cartilage condensation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate ISS evidence.
action: ACCEPT
reason: Core first step in chondrogenesis.
- term:
id: GO:0001894
label: tissue homeostasis
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate ISS evidence.
action: KEEP_AS_NON_CORE
reason: Peripheral maintenance function.
- term:
id: GO:0002683
label: negative regulation of immune system process
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate ISS evidence.
action: KEEP_AS_NON_CORE
reason: Peripheral immunomodulatory effect.
- term:
id: GO:0003170
label: heart valve development
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate ISS evidence.
action: KEEP_AS_NON_CORE
reason: Peripheral developmental function.
- term:
id: GO:0030279
label: negative regulation of ossification
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate ISS evidence.
action: ACCEPT
reason: Core mechanism for maintaining cartilage.
- term:
id: GO:0030850
label: prostate gland development
evidence_type: IEP
original_reference_id: PMID:20103652
review:
summary: IEP evidence for prostate development.
action: KEEP_AS_NON_CORE
reason: Peripheral epithelial development.
supported_by:
- reference_id: PMID:20103652
supporting_text: 2010 Jan 26. SOX9 elevation in the prostate promotes
proliferation and cooperates with PTEN loss to drive tumor formation.
- term:
id: GO:0050679
label: positive regulation of epithelial cell proliferation
evidence_type: IEP
original_reference_id: PMID:20103652
review:
summary: IEP evidence from prostate study.
action: KEEP_AS_NON_CORE
reason: Context-specific epithelial proliferation, not core function.
supported_by:
- reference_id: PMID:20103652
supporting_text: 2010 Jan 26. SOX9 elevation in the prostate promotes
proliferation and cooperates with PTEN loss to drive tumor formation.
- term:
id: GO:0070168
label: negative regulation of biomineral tissue development
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate ISS evidence.
action: ACCEPT
reason: Core mechanism for maintaining cartilage.
- term:
id: GO:0071347
label: cellular response to interleukin-1
evidence_type: IEP
original_reference_id: PMID:20079164
review:
summary: SOX9 responds to IL-1 in intervertebral disc cells.
action: KEEP_AS_NON_CORE
reason: Context-specific response in pathological conditions, not core
function.
supported_by:
- reference_id: PMID:20079164
supporting_text: Interleukin-1 inhibits Sox9 and collagen type II
expression via nuclear factor-kappaB in the cultured human
intervertebral disc cells.
- term:
id: GO:0001708
label: cell fate specification
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: |
SOX9 specifies cell fates including chondrocyte, glial, and Sertoli cell fates.
action: ACCEPT
reason: |
Cell fate specification is fundamental to SOX9's function as a lineage-determining
transcription factor in chondrocytes and glia. This is core.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: essential for lineage specification... glial fate
specification
- term:
id: GO:0001837
label: epithelial to mesenchymal transition
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: SOX9 is involved in EMT in various developmental contexts.
action: KEEP_AS_NON_CORE
reason: |
EMT is a process that occurs in multiple developmental contexts but is not a
core defining function of SOX9.
- term:
id: GO:0001942
label: hair follicle development
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: SOX9 plays roles in hair follicle development.
action: KEEP_AS_NON_CORE
reason: |
Hair follicle development is peripheral epithelial function noted in deep research
as one of multiple other programs.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: Hair follicle morphogenesis
- term:
id: GO:0002053
label: positive regulation of mesenchymal cell proliferation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: SOX9 promotes mesenchymal cell proliferation.
action: KEEP_AS_NON_CORE
reason: |
While related to chondrogenesis (mesenchymal condensation), this generic
proliferation term is broader than the specific chondrocyte proliferation that
is core.
- term:
id: GO:0003179
label: heart valve morphogenesis
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate ISS evidence for heart valve.
action: KEEP_AS_NON_CORE
reason: Peripheral developmental function.
- term:
id: GO:0003203
label: endocardial cushion morphogenesis
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: SOX9 involved in heart cushion development.
action: KEEP_AS_NON_CORE
reason: Peripheral cardiac development function.
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:12420222
review:
summary: Multiple IDA evidence codes for nuclear localization.
action: ACCEPT
reason: Well-established with experimental evidence.
supported_by:
- reference_id: PMID:12420222
supporting_text: 'RAR agonists stimulate SOX9 gene expression in breast cancer
cell lines: evidence for a role in retinoid-mediated growth inhibition.'
- term:
id: GO:0007283
label: spermatogenesis
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: SOX9 involved in spermatogenesis via Sertoli cell function.
action: KEEP_AS_NON_CORE
reason: Peripheral reproductive developmental function.
- term:
id: GO:0010564
label: regulation of cell cycle process
evidence_type: IMP
original_reference_id: PMID:12420222
review:
summary: SOX9 can regulate cell cycle in certain contexts.
action: KEEP_AS_NON_CORE
reason: |
While SOX9 affects proliferation in chondrocytes, this generic cell cycle term
is overly broad and not a core defining function.
supported_by:
- reference_id: PMID:12420222
supporting_text: 'RAR agonists stimulate SOX9 gene expression in breast cancer
cell lines: evidence for a role in retinoid-mediated growth inhibition.'
- term:
id: GO:0019100
label: male germ-line sex determination
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: SOX9 is critical for male sex determination.
action: KEEP_AS_NON_CORE
reason: Important but peripheral to core cartilage/glial functions.
- term:
id: GO:0030858
label: positive regulation of epithelial cell differentiation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: SOX9 promotes epithelial differentiation in multiple organs.
action: KEEP_AS_NON_CORE
reason: Generic epithelial differentiation is peripheral to core functions.
- term:
id: GO:0030916
label: otic vesicle formation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: SOX9 involved in inner ear development.
action: KEEP_AS_NON_CORE
reason: Peripheral sensory organ development.
- term:
id: GO:0032331
label: negative regulation of chondrocyte differentiation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: |
SOX9 can negatively regulate chondrocyte differentiation at certain stages to
maintain progenitor populations.
action: ACCEPT
reason: |
This reflects SOX9's context-dependent role in maintaining chondrocyte progenitors
versus promoting differentiation. Part of the nuanced chondrogenic program.
- term:
id: GO:0035019
label: somatic stem cell population maintenance
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: SOX9 maintains stem cell populations in various tissues.
action: KEEP_AS_NON_CORE
reason: |
While SOX9 can maintain stem/progenitor populations, this generic term doesn't
capture the core cartilage/glial functions.
- term:
id: GO:0042127
label: regulation of cell population proliferation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Very generic proliferation regulation term.
action: MARK_AS_OVER_ANNOTATED
reason: |
Too generic to be informative. More specific terms about chondrocyte proliferation
are preferred.
- term:
id: GO:0042981
label: regulation of apoptotic process
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: SOX9 may regulate apoptosis in certain contexts.
action: KEEP_AS_NON_CORE
reason: |
Apoptosis regulation is a peripheral effect, not a core transcription factor
function.
- term:
id: GO:0043066
label: negative regulation of apoptotic process
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: SOX9 may have anti-apoptotic effects.
action: KEEP_AS_NON_CORE
reason: Peripheral effect, not core function.
- term:
id: GO:0045662
label: negative regulation of myoblast differentiation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: SOX9 inhibits myoblast differentiation.
action: KEEP_AS_NON_CORE
reason: |
While SOX9 promotes chondrocyte over other mesenchymal fates, myoblast inhibition
is a peripheral effect.
- term:
id: GO:0046533
label: negative regulation of photoreceptor cell differentiation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: SOX9 involved in retinal development.
action: KEEP_AS_NON_CORE
reason: Peripheral retinal development function.
- term:
id: GO:0050679
label: positive regulation of epithelial cell proliferation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate ISS evidence.
action: KEEP_AS_NON_CORE
reason: Context-specific epithelial proliferation.
- term:
id: GO:0050680
label: negative regulation of epithelial cell proliferation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: SOX9 can also negatively regulate epithelial proliferation
contextually.
action: KEEP_AS_NON_CORE
reason: Context-dependent epithelial regulation, peripheral function.
- term:
id: GO:0051216
label: cartilage development
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate ISS evidence.
action: ACCEPT
reason: Core chondrogenic function.
- term:
id: GO:0060008
label: Sertoli cell differentiation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: SOX9 promotes Sertoli cell differentiation.
action: KEEP_AS_NON_CORE
reason: Peripheral sex determination function.
- term:
id: GO:0060041
label: retina development in camera-type eye
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: SOX9 involved in retinal development.
action: KEEP_AS_NON_CORE
reason: Peripheral sensory organ development.
- term:
id: GO:0060221
label: retinal rod cell differentiation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: More specific retinal development term.
action: KEEP_AS_NON_CORE
reason: Peripheral sensory cell differentiation.
- term:
id: GO:0060517
label: epithelial cell proliferation involved in prostatic bud elongation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Highly specific prostate development term.
action: KEEP_AS_NON_CORE
reason: Very specific peripheral developmental process.
- term:
id: GO:0060729
label: intestinal epithelial structure maintenance
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: SOX9 maintains intestinal epithelium.
action: KEEP_AS_NON_CORE
reason: Peripheral tissue maintenance function.
- term:
id: GO:0060784
label: regulation of cell proliferation involved in tissue homeostasis
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Generic tissue homeostasis proliferation regulation.
action: KEEP_AS_NON_CORE
reason: Peripheral maintenance function.
- term:
id: GO:0061138
label: morphogenesis of a branching epithelium
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate of earlier epithelial morphogenesis annotation.
action: KEEP_AS_NON_CORE
reason: Peripheral epithelial morphogenesis.
- term:
id: GO:0071300
label: cellular response to retinoic acid
evidence_type: IEP
original_reference_id: PMID:12420222
review:
summary: SOX9 responds to retinoic acid.
action: KEEP_AS_NON_CORE
reason: Contextual signaling response, not core function.
supported_by:
- reference_id: PMID:12420222
supporting_text: 'RAR agonists stimulate SOX9 gene expression in breast cancer
cell lines: evidence for a role in retinoid-mediated growth inhibition.'
- term:
id: GO:0072289
label: metanephric nephron tubule formation
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: More specific kidney development term.
action: KEEP_AS_NON_CORE
reason: Peripheral kidney development.
- term:
id: GO:0090090
label: negative regulation of canonical Wnt signaling pathway
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: SOX9 antagonizes Wnt/beta-catenin signaling.
action: ACCEPT
reason: |
Wnt/beta-catenin antagonism is a core mechanism by which SOX9 maintains chondrocyte
identity and blocks osteoblast differentiation.
supported_by:
- reference_id: file:human/SOX9/SOX9-deep-research-falcon.md
supporting_text: Antagonizes β-catenin in chondrocytes
- term:
id: GO:0090103
label: cochlea morphogenesis
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: SOX9 involved in inner ear cochlea development.
action: KEEP_AS_NON_CORE
reason: Peripheral sensory organ development.
- term:
id: GO:0001501
label: skeletal system development
evidence_type: IMP
original_reference_id: PMID:8640233
review:
summary: |
Broad term for skeletal development with IMP evidence from foundational SOX9
study.
action: ACCEPT
reason: |
Skeletal system development encompasses SOX9's chondrogenic functions. While
broad, this is a core developmental process for SOX9.
supported_by:
- reference_id: file:human/SOX9/SOX9-goa.tsv
supporting_text: GO:0001501 skeletal system development biological_process
ECO:0000315 IMP PMID:8640233
- reference_id: PMID:8640233
supporting_text: Sex reversal by loss of the C-terminal transactivation
domain of human SOX9.
- term:
id: GO:0003413
label: chondrocyte differentiation involved in endochondral bone
morphogenesis
evidence_type: IMP
original_reference_id: PMID:20676705
review:
summary: |
More specific term for chondrocyte differentiation in context of endochondral
ossification.
action: ACCEPT
reason: |
This captures the specific developmental context where SOX9-driven chondrogenesis
creates the cartilage template for bone formation. Core function.
supported_by:
- reference_id: file:human/SOX9/SOX9-goa.tsv
supporting_text: GO:0003413 chondrocyte differentiation involved in
endochondral bone morphogenesis biological_process ECO:0000315 IMP
PMID:20676705
- reference_id: PMID:20676705
supporting_text: 2010 Jul 30. Generation of transgenic mice for
conditional overexpression of Sox9.
- term:
id: GO:0003700
label: DNA-binding transcription factor activity
evidence_type: IMP
original_reference_id: PMID:8640233
review:
summary: IMP evidence from foundational study.
action: ACCEPT
reason: Core molecular function with experimental evidence.
supported_by:
- reference_id: PMID:8640233
supporting_text: Sex reversal by loss of the C-terminal transactivation
domain of human SOX9.
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:8640233
review:
summary: More IDA evidence for nuclear localization.
action: ACCEPT
reason: Well-established cellular component.
supported_by:
- reference_id: PMID:8640233
supporting_text: Sex reversal by loss of the C-terminal transactivation
domain of human SOX9.
- term:
id: GO:0008584
label: male gonad development
evidence_type: IMP
original_reference_id: PMID:8640233
review:
summary: IMP evidence for testis development.
action: KEEP_AS_NON_CORE
reason: Peripheral sex determination function.
supported_by:
- reference_id: PMID:8640233
supporting_text: Sex reversal by loss of the C-terminal transactivation
domain of human SOX9.
- term:
id: GO:0032332
label: positive regulation of chondrocyte differentiation
evidence_type: IMP
original_reference_id: PMID:20676705
review:
summary: More IMP evidence for core function.
action: ACCEPT
reason: Core chondrogenic function.
supported_by:
- reference_id: PMID:20676705
supporting_text: 2010 Jul 30. Generation of transgenic mice for
conditional overexpression of Sox9.
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:8640233
review:
summary: IDA evidence from foundational study.
action: ACCEPT
reason: Core transcriptional activator function.
supported_by:
- reference_id: PMID:8640233
supporting_text: Sex reversal by loss of the C-terminal transactivation
domain of human SOX9.
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:18512230
review:
summary: More IDA evidence for nucleus.
action: ACCEPT
reason: Well-established.
supported_by:
- reference_id: PMID:18512230
supporting_text: Quantitative assessment of glial cells in the human and
guinea pig enteric nervous system with an anti-Sox8/9/10 antibody.
- term:
id: GO:0000987
label: cis-regulatory region sequence-specific DNA binding
evidence_type: IDA
original_reference_id: PMID:10805756
review:
summary: IDA evidence for sequence-specific binding.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:10805756
supporting_text: Phosphorylation of SOX9 by cyclic AMP-dependent protein
kinase A enhances SOX9's ability to transactivate a Col2a1
chondrocyte-specific enhancer.
- term:
id: GO:0003700
label: DNA-binding transcription factor activity
evidence_type: IDA
original_reference_id: PMID:10805756
review:
summary: More IDA evidence.
action: ACCEPT
reason: Core molecular function.
supported_by:
- reference_id: PMID:10805756
supporting_text: Phosphorylation of SOX9 by cyclic AMP-dependent protein
kinase A enhances SOX9's ability to transactivate a Col2a1
chondrocyte-specific enhancer.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20530484
review:
summary: Another generic protein binding (MITF/OTX2 interactions).
action: REMOVE
reason: Generic protein binding term, uninformative.
supported_by:
- reference_id: PMID:20530484
supporting_text: Epub 2010 Jun 8. SOX9, through interaction with
microphthalmia-associated transcription factor (MITF) and OTX2,
regulates BEST1 expression in the retinal pigment epithelium.
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:10805756
review:
summary: More IDA evidence.
action: ACCEPT
reason: Well-established.
supported_by:
- reference_id: PMID:10805756
supporting_text: Phosphorylation of SOX9 by cyclic AMP-dependent protein
kinase A enhances SOX9's ability to transactivate a Col2a1
chondrocyte-specific enhancer.
- term:
id: GO:0032991
label: protein-containing complex
evidence_type: IDA
original_reference_id: PMID:20530484
review:
summary: |
SOX9 forms complexes with partners. This is a very generic cellular component
term.
action: MARK_AS_OVER_ANNOTATED
reason: |
Too generic. More specific terms like "transcription regulator complex" better
capture SOX9's complex formation.
supported_by:
- reference_id: PMID:20530484
supporting_text: Epub 2010 Jun 8. SOX9, through interaction with
microphthalmia-associated transcription factor (MITF) and OTX2,
regulates BEST1 expression in the retinal pigment epithelium.
- term:
id: GO:0034236
label: protein kinase A catalytic subunit binding
evidence_type: IPI
original_reference_id: PMID:10805756
review:
summary: |
SOX9 interacts with PKA which phosphorylates it to enhance activity. This is
a specific binding term.
action: ACCEPT
reason: |
PKA binding and phosphorylation is a specific regulatory mechanism for SOX9
activity. Unlike generic protein binding, this conveys functional information.
supported_by:
- reference_id: file:human/SOX9/SOX9-uniprot.txt
supporting_text: Phosphorylation at Ser-64 and Ser-211 by PKA increases
transcriptional activity
- reference_id: PMID:10805756
supporting_text: Phosphorylation of SOX9 by cyclic AMP-dependent protein
kinase A enhances SOX9's ability to transactivate a Col2a1
chondrocyte-specific enhancer.
- term:
id: GO:0045893
label: positive regulation of DNA-templated transcription
evidence_type: IDA
original_reference_id: PMID:10805756
review:
summary: IDA evidence for transcriptional activation.
action: ACCEPT
reason: Core activator function.
supported_by:
- reference_id: PMID:10805756
supporting_text: Phosphorylation of SOX9 by cyclic AMP-dependent protein
kinase A enhances SOX9's ability to transactivate a Col2a1
chondrocyte-specific enhancer.
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:20530484
review:
summary: More IDA evidence.
action: ACCEPT
reason: Core function.
supported_by:
- reference_id: PMID:20530484
supporting_text: Epub 2010 Jun 8. SOX9, through interaction with
microphthalmia-associated transcription factor (MITF) and OTX2,
regulates BEST1 expression in the retinal pigment epithelium.
- term:
id: GO:0065003
label: protein-containing complex assembly
evidence_type: IDA
original_reference_id: PMID:20530484
review:
summary: SOX9 assembles into protein complexes.
action: KEEP_AS_NON_CORE
reason: |
While SOX9 does form complexes, this generic assembly term doesn't capture the
core transcription factor function.
supported_by:
- reference_id: PMID:20530484
supporting_text: Epub 2010 Jun 8. SOX9, through interaction with
microphthalmia-associated transcription factor (MITF) and OTX2,
regulates BEST1 expression in the retinal pigment epithelium.
- term:
id: GO:0007165
label: signal transduction
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate of earlier very generic signal transduction term.
action: MARK_AS_OVER_ANNOTATED
reason: Too generic to be informative.
- term:
id: GO:0072034
label: renal vesicle induction
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate kidney development term.
action: KEEP_AS_NON_CORE
reason: Peripheral kidney development.
- term:
id: GO:0090184
label: positive regulation of kidney development
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate kidney development term.
action: KEEP_AS_NON_CORE
reason: Peripheral kidney development.
- term:
id: GO:0090190
label: positive regulation of branching involved in ureteric bud
morphogenesis
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Duplicate kidney branching term.
action: KEEP_AS_NON_CORE
reason: Peripheral kidney development.
- term:
id: GO:0008584
label: male gonad development
evidence_type: IEP
original_reference_id: PMID:17848411
review:
summary: IEP evidence for testis development.
action: KEEP_AS_NON_CORE
reason: Peripheral sex determination function.
supported_by:
- reference_id: PMID:17848411
supporting_text: Epub 2007 Sep 11. Developmental changes in human fetal
testicular cell numbers and messenger ribonucleic acid levels during the
second trimester.
references:
- id: GO_REF:0000024
title: Manual transfer of experimentally-verified manual GO annotation data to
orthologs by curator judgment of sequence similarity
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000043
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
findings: []
- id: GO_REF:0000052
title: Gene Ontology annotation based on curation of immunofluorescence data
findings: []
- id: GO_REF:0000107
title: Automatic transfer of experimentally verified manual GO annotation data
to orthologs using Ensembl Compara
findings: []
- id: GO_REF:0000113
title: Gene Ontology annotation of human sequence-specific DNA binding
transcription factors (DbTFs) based on the TFClass database
findings: []
- id: GO_REF:0000117
title: Electronic Gene Ontology annotations created by ARBA machine learning
models
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: SOX9-deep-research-falcon.md
title: Deep research report on SOX9 molecular function and pathways
findings:
- statement: SOX9 is a SOXE-family transcription factor that binds AACAAT
motifs
- statement: Functions in nucleus with nuclear localization signals
- statement: Cooperates with SOX5/6 on paired SOX sites for cartilage genes
- statement: Recruits co-activators CBP/p300 and TIP60
- statement: Antagonizes beta-catenin in chondrocytes
- statement: Core functions are chondrogenesis and gliogenesis/oligodendrocyte
differentiation
- id: file:human/SOX9/SOX9-uniprot.txt
title: UniProt entry for human SOX9
findings:
- statement: Contains HMG-box DNA-binding domain (residues 105-173)
- statement: Transcription factor that plays key role in chondrocyte
differentiation
- statement: Binds 5'-ACAAAG-3' DNA motif in enhancers
- statement: Nuclear localization
- statement: Homodimerization required for activity
- statement: Has transactivation domains TAM and TAC
- statement: Phosphorylation by PKA increases transcriptional activity
- statement: Antagonizes beta-catenin signaling
- id: SOX9-goa.tsv
title: GO annotations for SOX9 from GOA file
findings:
- statement: Multiple IDA/IMP/ISS evidence codes for chondrocyte
differentiation
- statement: IDA evidence for transcription factor activity
- statement: Nuclear localization validated
- statement: Multiple experimental evidence codes for transcriptional
activation
- id: PMID:8640233
title: Sex reversal by loss of the C-terminal transactivation domain of human
SOX9.
findings: []
- id: PMID:10805756
title: Phosphorylation of SOX9 by cyclic AMP-dependent protein kinase A
enhances SOX9's ability to transactivate a Col2a1 chondrocyte-specific
enhancer.
findings: []
- id: PMID:12420222
title: 'RAR agonists stimulate SOX9 gene expression in breast cancer cell lines:
evidence for a role in retinoid-mediated growth inhibition.'
findings: []
- id: PMID:12810722
title: A SOX9 defect of calmodulin-dependent nuclear import in campomelic
dysplasia/autosomal sex reversal.
findings: []
- id: PMID:17848411
title: Developmental changes in human fetal testicular cell numbers and
messenger ribonucleic acid levels during the second trimester.
findings: []
- id: PMID:18512230
title: Quantitative assessment of glial cells in the human and guinea pig
enteric nervous system with an anti-Sox8/9/10 antibody.
findings: []
- id: PMID:20079164
title: Interleukin-1 inhibits Sox9 and collagen type II expression via nuclear
factor-kappaB in the cultured human intervertebral disc cells.
findings: []
- id: PMID:20103652
title: SOX9 elevation in the prostate promotes proliferation and cooperates
with PTEN loss to drive tumor formation.
findings: []
- id: PMID:20484372
title: The dimerization domain of SOX9 is required for transcription
activation of a chondrocyte-specific chromatin DNA template.
findings: []
- id: PMID:20530484
title: SOX9, through interaction with microphthalmia-associated transcription
factor (MITF) and OTX2, regulates BEST1 expression in the retinal pigment
epithelium.
findings: []
- id: PMID:20651055
title: Upregulation of SOX9 in lung adenocarcinoma and its involvement in the
regulation of cell growth and tumorigenicity.
findings: []
- id: PMID:20676705
title: Generation of transgenic mice for conditional overexpression of Sox9.
findings: []
- id: PMID:21346191
title: Arid5a cooperates with Sox9 to stimulate chondrocyte-specific
transcription.
findings: []
- id: PMID:21367821
title: Sox9 sustains chondrocyte survival and hypertrophy in part through
Pik3ca-Akt pathways.
findings: []
- id: PMID:21401405
title: Electroporation-mediated transfer of SOX trio genes (SOX-5, SOX-6, and
SOX-9) to enhance the chondrogenesis of mesenchymal stem cells.
findings: []
- id: PMID:21412441
title: Failure of SOX9 regulation in 46XY disorders of sex development with
SRY, SOX9 and SF1 mutations.
findings: []
- id: PMID:21512138
title: An EGFR-ERK-SOX9 signaling cascade links urothelial development and
regeneration to cancer.
findings: []
- id: PMID:22110751
title: Inhibitory role of Notch1 in calcific aortic valve disease.
findings: []
- id: PMID:24014021
title: miR-1247 functions by targeting cartilage transcription factor SOX9.
findings: []
- id: PMID:24681825
title: The NLR-related protein NWD1 is associated with prostate cancer and
modulates androgen receptor signaling.
findings: []
- id: PMID:26634652
title: Valve Endothelial Cell-Derived Tgfβ1 Signaling Promotes Nuclear
Localization of Sox9 in Interstitial Cells Associated With Attenuated
Calcification.
findings: []
- id: PMID:26687115
title: The microRNA-29 family in cartilage homeostasis and osteoarthritis.
findings: []
- id: PMID:28263186
title: Loss of DDRGK1 modulates SOX9 ubiquitination in spondyloepimetaphyseal
dysplasia.
findings: []
- id: PMID:28473536
title: Impact of cytosine methylation on DNA binding specificities of human
transcription factors.
findings: []
- id: PMID:29503843
title: Sox9 augments BMP2-induced chondrogenic differentiation by
downregulating Smad7 in mesenchymal stem cells (MSCs).
findings: []
- id: PMID:31194875
title: The SOXE transcription factors-SOX8, SOX9 and SOX10-share a bi-partite
transactivation mechanism.
findings: []
- id: Reactome:R-HSA-5626938
title: Reactome pathway reference
findings: []
- id: Reactome:R-HSA-8985343
title: Reactome pathway reference
findings: []
- id: file:human/SOX9/SOX9-deep-research-falcon.md
title: Deep research report on SOX9
findings: []
core_functions: []