ASCL1 (Achaete-scute homolog 1, also known as MASH1/hASH1) is a proneural basic helix-loop-helix (bHLH) transcription factor that functions as both a classical transcriptional activator and a pioneer factor capable of accessing closed chromatin. It binds E-box motifs (CANNTG, particularly CACCTG) as a heterodimer with E-proteins (TCF3/E12/E47, TCF4) to activate neuronal and neuroendocrine gene programs. ASCL1 plays essential roles in neuronal differentiation, neuronal fate commitment, and neuroendocrine cell development. It is a master regulator of the SCLC-A (neuroendocrine) subtype of small cell lung cancer and directly activates targets including INSM1, MYT1, DLL1, and DLL3 (Notch pathway modulators). ASCL1 protein stability is regulated by CDK2-CyclinA2 phosphorylation, HUWE1-mediated ubiquitination, and protection via E-protein heterodimerization.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0030182 neuron differentiation | IBA GO_REF:0000033 | ACCEPT | Summary: Neuron differentiation is a core function of ASCL1. The IBA annotation is well-supported by phylogenetic analysis and extensive experimental evidence. ASCL1 (MASH1) is essential for proper development of olfactory and autonomic neurons and for neuronal differentiation in the CNS and PNS (PMID:10903890). ASCL1 overexpression increases neurogenesis in human neural progenitor cells (PMID:19008346). Reason: This is a core function of ASCL1. The protein is classified as a proneural bHLH transcription factor whose primary role is driving neuronal differentiation. Multiple experimental studies confirm this function, and the IBA phylogenetic inference is consistent with the extensive literature. Supporting Evidence: PMID:10903890 The basic helix-loop-helix (bHLH) transcription factor mammalian achaete-scute homolog-1 (MASH-1 in mouse and HASH-1 in human) is essential for proper development of olfactory and most peripheral autonomic neurons, and for the formation of distinct neuronal circuits within the central nervous system. PMID:19008346 By overexpressing one of these, the transcription factor ASCL1, we were able to regain neurogenesis from hNPC(VM) cultures file:human/ASCL1/ASCL1-deep-research-cyberian.md model: deep-research |
| GO:0007423 sensory organ development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: ASCL1 is essential for development of olfactory neurons, which are part of the olfactory sensory organ system. The IBA annotation captures the role in sensory (specifically olfactory) development. Reason: While ASCL1 is essential for olfactory neuron development (a sensory system), this is a more peripheral consequence of its neuronal differentiation function rather than a core molecular function. The term is appropriate but represents a downstream developmental phenotype. Supporting Evidence: PMID:10903890 The basic helix-loop-helix (bHLH) transcription factor mammalian achaete-scute homolog-1 (MASH-1 in mouse and HASH-1 in human) is essential for proper development of olfactory and most peripheral autonomic neurons, and for the formation of distinct neuronal circuits within the central nervous system. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: ASCL1 is a transcriptional activator that transactivates E-box containing reporter constructs (PMID:10903890). It drives transcription of neuronal and neuroendocrine gene programs. Reason: This is a core function. ASCL1 functions as a transcriptional activator, directly demonstrated by reporter assays showing transactivation of E-box containing constructs when complexed with E-proteins like E2-2/TCF4. Supporting Evidence: PMID:10903890 The HASH-1/E2-2 complex binds an E-box (CACCTG) in vitro, and transactivates an E-box containing reporter construct in vivo. |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: ASCL1 binds sequence-specifically to E-box elements (CANNTG, particularly CACCTG) in promoter and enhancer regions. This DNA binding is essential for its transcription factor activity. Reason: This is a core molecular function. Multiple studies demonstrate E-box binding by gel shift assays and functional studies. ASCL1 binds as a heterodimer with E-proteins to specific DNA sequences. Supporting Evidence: PMID:10903890 The HASH-1/E2-2 complex binds an E-box (CACCTG) in vitro PMID:11736660 Binding of hASH-1 to the E-box cluster was confirmed by gel mobility-shift assay. |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: ASCL1 is a DNA-binding transcription factor that regulates RNA polymerase II-dependent transcription. This is the fundamental molecular function of ASCL1 as a bHLH transcription factor. Reason: This is the core molecular function of ASCL1. It binds DNA via its bHLH domain as a heterodimer with E-proteins and regulates transcription of target genes. IDA evidence also supports this (PMID:10903890). Supporting Evidence: PMID:10903890 The HASH-1/E2-2 complex binds an E-box (CACCTG) in vitro, and transactivates an E-box containing reporter construct in vivo. |
| GO:0090575 RNA polymerase II transcription regulator complex | IBA GO_REF:0000033 | ACCEPT | Summary: ASCL1 functions as part of a transcriptional regulatory complex, forming heterodimers with E-proteins (TCF3, TCF4) and interacting with chromatin remodeling complexes (mSWI/SNF via ARID1A, SMARCC1). Reason: ASCL1 functions in transcription regulator complexes. It heterodimerizes with E-proteins for DNA binding and interacts with mSWI/SNF chromatin remodeling complexes (PMID:36931659). UniProt records interactions with TCF3, TCF4, ARID1A, and SMARCC1. Supporting Evidence: PMID:10903890 E2-2 forms a functional complex with HASH-1 PMID:36931659 ASCL1 interacts with BAF SWI/SNF chromatin remodeling complexes |
| GO:0050767 regulation of neurogenesis | IBA GO_REF:0000033 | ACCEPT | Summary: ASCL1 is a master regulator of neurogenesis. Overexpression increases neurogenesis (PMID:19008346), and it is required for neuronal differentiation from progenitor cells. Reason: This is a core biological process for ASCL1. The IBA annotation is well-supported by extensive experimental evidence showing ASCL1 positively regulates neurogenesis. Supporting Evidence: PMID:19008346 Regionally specified human neural progenitor cells derived from the mesencephalon and forebrain undergo increased neurogenesis following overexpression of ASCL1. |
| GO:0003677 DNA binding | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | Summary: ASCL1 binds DNA via its bHLH domain. This IEA annotation based on UniProt keywords is correct but less specific than other available annotations (E-box binding, sequence-specific DNA binding). Reason: While correct, this term is too general. More specific terms like E-box binding (GO:0070888) and sequence-specific double-stranded DNA binding (GO:1990837) are available and already annotated with experimental evidence. Proposed replacements: E-box binding sequence-specific double-stranded DNA binding |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000120 | ACCEPT | Summary: ASCL1 is a DNA-binding transcription factor. This IEA annotation is correct and supported by IDA evidence from PMID:10903890. Reason: This is a core molecular function. The IEA annotation is correct and redundant with the IDA annotation from PMID:10903890, which provides experimental support. Supporting Evidence: PMID:10903890 The HASH-1/E2-2 complex binds an E-box (CACCTG) in vitro, and transactivates an E-box containing reporter construct in vivo. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: ASCL1 localizes to the nucleus where it functions as a transcription factor. This is supported by multiple IDA annotations (PMID:12858003, PMID:17507989, PMID:18311112). Reason: Nuclear localization is essential for ASCL1 function as a transcription factor. The IEA annotation is correct and supported by multiple IDA annotations from immunohistochemistry studies. Supporting Evidence: PMID:12858003 Immunohistochemically, pulmonary neuroendocrine cells (PNECs) are positive for Mash1 |
| GO:0006357 regulation of transcription by RNA polymerase II | IEA GO_REF:0000002 | ACCEPT | Summary: ASCL1 regulates transcription by RNA polymerase II, functioning as both an activator and repressor depending on context and target gene. Reason: This is a core function of ASCL1. It regulates transcription both positively (neuronal genes) and negatively (e.g., PACE4 gene). The IEA annotation is appropriate. Supporting Evidence: PMID:10903890 transactivates an E-box containing reporter construct in vivo PMID:11736660 The overexpression of hASH-1 or MASH-1 causes a marked decrease in endogenous PACE4 gene expression |
| GO:0007399 nervous system development | IEA GO_REF:0000120 | ACCEPT | Summary: ASCL1 is essential for nervous system development, particularly neuronal differentiation in CNS and PNS. Reason: This is a core biological process. ASCL1 is essential for CNS and PNS neuron development. More specific child terms are also annotated, but this broader term is appropriate as a summary. Supporting Evidence: PMID:10903890 essential for proper development of olfactory and most peripheral autonomic neurons, and for the formation of distinct neuronal circuits within the central nervous system |
| GO:0030154 cell differentiation | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | Summary: ASCL1 drives cell differentiation, specifically neuronal and neuroendocrine differentiation. Reason: While correct, this term is too general. More specific terms like neuron differentiation (GO:0030182) and neuroendocrine cell differentiation are more appropriate and already annotated. Proposed replacements: neuron differentiation |
| GO:0046983 protein dimerization activity | IEA GO_REF:0000002 | ACCEPT | Summary: ASCL1 forms heterodimers with E-proteins (TCF3, TCF4) via its HLH domain. This dimerization is essential for DNA binding and transcriptional activity. Reason: Dimerization is essential for ASCL1 function. It heterodimerizes with E-proteins to bind DNA. UniProt documents interactions with TCF3 and TCF4 with multiple experiments. Supporting Evidence: PMID:10903890 E2-2 interacts with HASH-1 in both yeast and mammalian cells. The HASH-1/E2-2 complex binds an E-box |
| GO:0070888 E-box binding | IEA GO_REF:0000117 | ACCEPT | Summary: ASCL1 binds E-box motifs (CANNTG, specifically CACCTG). This is demonstrated by gel shift assays and is essential for its transcription factor activity. Reason: E-box binding is a core molecular function of ASCL1. This IEA annotation is correct and supported by IDA annotations from PMID:10903890 and PMID:11736660. Supporting Evidence: PMID:10903890 The HASH-1/E2-2 complex binds an E-box (CACCTG) in vitro PMID:11736660 Binding of hASH-1 to the E-box cluster was confirmed by gel mobility-shift assay |
| GO:0005515 protein binding | IPI PMID:10903890 HASH-1 and E2-2 are expressed in human neuroblastoma cells a... | REMOVE | Summary: This annotation captures protein-protein interaction with E2-2/TCF4, identified by yeast two-hybrid. However, a more specific term (bHLH transcription factor binding) is available and annotated. Reason: The generic "protein binding" term is uninformative. The specific interaction with E2-2 is better captured by GO:0043425 (bHLH transcription factor binding) which is also annotated from this reference. Proposed replacements: bHLH transcription factor binding Supporting Evidence: PMID:10903890 HASH-1 and E2-2 are expressed in human neuroblastoma cells and form a functional complex. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: This annotation is from the HuRI high-throughput protein interactome study. While the interactions are likely valid, "protein binding" is uninformative without specifying the binding partner. Reason: Generic "protein binding" annotations from high-throughput studies provide limited functional insight. The term is too broad to be useful for understanding ASCL1 function. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: This annotation is from the BioPlex proteome-scale network study. While interactions are documented, the generic term provides no specific functional information. Reason: Generic "protein binding" from high-throughput AP-MS studies is uninformative. More specific interaction terms should be used where the functional relevance is understood. Supporting Evidence: PMID:33961781 2021 May 6. Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. |
| GO:0005515 protein binding | IPI PMID:36931659 Pioneer factor ASCL1 cooperates with the mSWI/SNF complex at... | MODIFY | Summary: This study demonstrates ASCL1 interaction with mSWI/SNF chromatin remodeling complexes (ARID1A, SMARCC1). The specific functional context (chromatin remodeling cooperation) is known. Reason: The interaction with mSWI/SNF components is functionally relevant (pioneer factor activity with chromatin remodelers). A more specific term capturing the chromatin remodeling complex interaction would be more informative. Proposed replacements: DNA-binding transcription factor binding Supporting Evidence: PMID:36931659 ASCL1 interacts with BAF SWI/SNF chromatin remodeling complexes, primarily at targets where it acts as a nonpioneer factor |
| GO:0003358 noradrenergic neuron development | IEA GO_REF:0000107 | ACCEPT | Summary: ASCL1 is required for noradrenergic neuron development, as demonstrated by mutation studies in congenital central hypoventilation syndrome patients (PMID:14532329). Reason: This is a core biological process. HASH-1 mutations impair noradrenergic neuronal development in an in vitro model system, demonstrating the requirement for ASCL1 in this process. Supporting Evidence: PMID:14532329 All HASH-1 mutant alleles impaired noradrenergic neuronal development, when overexpressed from adenoviral constructs. |
| GO:0003682 chromatin binding | IEA GO_REF:0000107 | ACCEPT | Summary: ASCL1 exhibits pioneer factor activity, binding nucleosomal DNA and remodeling chromatin at neuronal enhancers. This is demonstrated by PMID:36931659. Reason: Chromatin binding is a core function of ASCL1 as a pioneer transcription factor. It binds nucleosomal DNA and cooperates with mSWI/SNF to remodel chromatin. Supporting Evidence: PMID:36931659 Pioneer transcription factors are thought to play pivotal roles in developmental processes by binding nucleosomal DNA to activate gene expression |
| GO:0003690 double-stranded DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: ASCL1 binds double-stranded DNA at E-box motifs. This is demonstrated by gel shift assays and functional studies. Reason: This is a valid molecular function. ASCL1 binds dsDNA as a heterodimer with E-proteins. More specific IDA annotations exist (sequence-specific double-stranded DNA binding). Supporting Evidence: PMID:11736660 Binding of hASH-1 to the E-box cluster was confirmed by gel mobility-shift assay |
| GO:0007507 heart development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: This annotation is transferred from mouse/rat orthologs via Ensembl Compara. While ASCL1 may have some role in cardiac development (possibly via autonomic innervation), this is not a well-characterized primary function of human ASCL1. Reason: Heart development is not a primary function of ASCL1. Any role is likely secondary to autonomic nervous system development. The annotation is not wrong but represents a peripheral/indirect function. |
| GO:0021879 forebrain neuron differentiation | IEA GO_REF:0000107 | ACCEPT | Summary: ASCL1 is expressed in forebrain and drives neuron differentiation there, including GABAergic interneuron differentiation (PMID:12050665). Reason: This is a specific manifestation of ASCL1's neuronal differentiation function in the forebrain. Supported by evidence showing ASCL1/Mash1 expression in cortical progenitors. Supporting Evidence: PMID:12050665 One lineage expresses Dlx1/2 and Mash1 transcription factors, represents 65% of neocortical GABAergic neurons in humans, and originates from Mash1-expressing progenitors of the neocortical ventricular and subventricular zone of the dorsal forebrain. |
| GO:0030182 neuron differentiation | IEA GO_REF:0000107 | ACCEPT | Summary: Duplicate annotation of neuron differentiation via Ensembl Compara transfer. The IBA annotation already captures this function with phylogenetic support. Reason: This is a core function. Duplicate with IBA annotation but both are valid. The multiple evidence codes reinforce the importance of this function. Supporting Evidence: PMID:10903890 essential for proper development of olfactory and most peripheral autonomic neurons |
| GO:0032526 response to retinoic acid | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ASCL1 expression is regulated in response to retinoic acid treatment. In SH-SY5Y neuroblastoma cells, ASCL1 expression is reduced after RA treatment as cells differentiate (PMID:12000752). Reason: ASCL1 responds to retinoic acid (expression is downregulated during RA-induced differentiation), but this is a regulatory response rather than a core function. IEP evidence exists (PMID:12000752). Supporting Evidence: PMID:12000752 expression of neuroblast-specific ASCL1 (HASH-1) gene was promptly reduced after RA treatment |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | MODIFY | Summary: ASCL1 may form homodimers, though heterodimerization with E-proteins is the functionally characterized interaction mode for DNA binding. Reason: ASCL1 binds DNA functionally only as a heterodimer with class I E-proteins (TCF3/E2A, TCF4/E2-2, TCF12/HEB), not as a homodimer. The IEA GO:0042802 (identical protein binding) derives from automated Ensembl Compara ortholog transfer and implies a homodimer, whereas all experimentally validated evidence supports E-protein heterodimerization. An OpenScientist run synthesizing structural, biochemical, evolutionary and regulatory evidence recommends replacing GO:0042802 with GO:0046982 (protein heterodimerization activity); homodimers form only in vitro under artificial conditions and have never been shown to bind DNA or function in vivo. Proposed replacements: protein heterodimerization activity Supporting Evidence: file:human/ASCL1/ASCL1-hypotheses/dna-binding-mode-eprotein-heterodimer/openscientist.md GO:0042802 should be removed and replaced with GO:0046982 (protein heterodimerization activity) file:human/ASCL1/ASCL1-hypotheses/dna-binding-mode-eprotein-heterodimer/openscientist.md ASCL1's functional DNA-binding mode is heterodimerization with class I E-proteins such as TCF3/E2A (products E12 and E47), TCF4/E2-2, and TCF12/HEB. |
| GO:0043025 neuronal cell body | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ASCL1 is expressed in neuronal cell bodies during development. As a transcription factor, it is primarily nuclear within these cells. Reason: The cellular component annotation is technically correct but less informative than "nucleus." ASCL1 is found in neuronal progenitors and differentiating neurons, localized to the nucleus. |
| GO:0043565 sequence-specific DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: ASCL1 binds DNA in a sequence-specific manner, recognizing E-box motifs. This is well-supported by experimental evidence. Reason: Sequence-specific DNA binding is a core molecular function. IDA evidence exists for the more specific term (sequence-specific double-stranded DNA binding) from PMID:28473536. Supporting Evidence: PMID:10903890 The HASH-1/E2-2 complex binds an E-box (CACCTG) in vitro |
| GO:0045665 negative regulation of neuron differentiation | IEA GO_REF:0000107 | REMOVE | Summary: This annotation appears contradictory since ASCL1 is primarily a positive regulator of neuron differentiation. The IDA annotation from PMID:12000752 appears to be an error in interpretation. Reason: ASCL1 is primarily a positive regulator of neuronal differentiation. The cited evidence (PMID:12000752) shows ASCL1 is downregulated during differentiation, which is different from ASCL1 negatively regulating differentiation. This annotation appears to be an error. |
| GO:0045666 positive regulation of neuron differentiation | IEA GO_REF:0000107 | ACCEPT | Summary: ASCL1 positively regulates neuron differentiation. This is the core function of ASCL1 as a proneural transcription factor. Reason: This is a core function. ASCL1 overexpression increases neurogenesis, and it is required for neuronal differentiation in multiple lineages. Supporting Evidence: PMID:19008346 By overexpressing one of these, the transcription factor ASCL1, we were able to regain neurogenesis from hNPC(VM) cultures |
| GO:0045686 negative regulation of glial cell differentiation | TAS PMID:17166924 Ascl1 defines sequentially generated lineage-restricted neur... | NEW | Summary: ASCL1 suppresses glial (astrocyte) fate, promoting neuronal and oligodendrocyte lineages over astroglial lineage. Genetic fate mapping shows ASCL1 is present in progenitors to neurons and oligodendrocytes but not astrocytes. Reason: ASCL1 actively suppresses gliogenesis (specifically astrocyte differentiation) as part of its role in the neuron-glia binary fate decision. Ascl1-null cells have diminished neuronal differentiation capacity and retain characteristics of immature glial cells (PMID:17166924). This annotation is missing and represents a core function of ASCL1 in lineage specification. Supporting Evidence: PMID:17166924 We find that Ascl1 is present in progenitors to both neurons and oligodendrocytes, but not astrocytes. |
| GO:0048663 neuron fate commitment | IEA GO_REF:0000107 | ACCEPT | Summary: ASCL1 is required for neuron fate commitment, functioning early in neurogenesis to commit progenitors to neuronal lineages. Reason: Neuron fate commitment is a core function. ASCL1 expression marks the transition from cycling progenitors to postmitotic neurons (PMID:36931659). Supporting Evidence: PMID:36931659 endogenous expression of ASCL1 drives progenitor differentiation |
| GO:0048665 neuron fate specification | IEA GO_REF:0000107 | ACCEPT | Summary: ASCL1 specifies neuronal fate, particularly GABAergic interneurons in the cortex and noradrenergic neurons in the autonomic nervous system. Reason: Neuron fate specification is a core function. ASCL1 specifies particular neuronal subtypes including GABAergic interneurons (PMID:12050665) and noradrenergic neurons (PMID:14532329). Supporting Evidence: PMID:12050665 One lineage expresses Dlx1/2 and Mash1 transcription factors PMID:14532329 All HASH-1 mutant alleles impaired noradrenergic neuronal development |
| GO:0048666 neuron development | IEA GO_REF:0000107 | ACCEPT | Summary: ASCL1 is essential for neuron development broadly, encompassing differentiation and maturation. Reason: Neuron development is a core function. This broader term encompasses the more specific neuronal differentiation and fate commitment functions. Supporting Evidence: PMID:10903890 essential for proper development of olfactory and most peripheral autonomic neurons |
| GO:0051593 response to folic acid | IEA GO_REF:0000107 | UNDECIDED | Summary: This annotation is transferred from model organisms. The functional relevance to human ASCL1 is unclear without supporting literature. Reason: Unable to verify relevance of folic acid response for human ASCL1 without access to the primary evidence. This may represent a peripheral phenotype from model organisms. |
| GO:0060579 ventral spinal cord interneuron fate commitment | IEA GO_REF:0000107 | ACCEPT | Summary: ASCL1 functions with FOXN4 in specifying V2b interneurons in the spinal cord, as documented in UniProt and ISS annotations. Reason: This is a specific neuronal fate commitment function supported by the UniProt record stating ASCL1 acts synergistically with FOXN4 to specify V2b neurons from p2 progenitors. Supporting Evidence: UniProt:P50553 Acts synergistically with FOXN4 to specify the identity of V2b neurons rather than V2a from bipotential p2 progenitors during spinal cord neurogenesis |
| GO:0061549 sympathetic ganglion development | IEA GO_REF:0000107 | ACCEPT | Summary: ASCL1 is required for sympathetic nervous system development, including sympathetic ganglia. This is supported by NAS evidence from PMID:10903890. Reason: Sympathetic ganglion development is related to the autonomic neuron development function of ASCL1, which is well-documented. Supporting Evidence: PMID:10903890 essential for proper development of... most peripheral autonomic neurons |
| GO:0070849 response to epidermal growth factor | IEA GO_REF:0000107 | UNDECIDED | Summary: This annotation is transferred from model organisms. The functional relevance to human ASCL1 is unclear without supporting literature. Reason: Unable to verify relevance of EGF response for human ASCL1 without access to primary evidence. May represent regulatory effects on ASCL1 expression rather than a core function. |
| GO:0071259 cellular response to magnetism | IEA GO_REF:0000107 | UNDECIDED | Summary: This is an unusual annotation likely transferred from a specific study. The functional relevance is unclear and this does not represent a core ASCL1 function. Reason: This appears to be a highly specific phenotype from model organism studies. Without access to the primary evidence, cannot evaluate the relevance to human ASCL1 function. |
| GO:0003676 nucleic acid binding | EXP PMID:28402879 Fragment-Based NMR Study of the Conformational Dynamics in t... | MARK AS OVER ANNOTATED | Summary: This NMR study characterized the conformational dynamics of ASCL1 protein. While it confirms DNA binding capacity, the term is too general given the available specific annotations. Reason: The term "nucleic acid binding" is too general. ASCL1 specifically binds double-stranded DNA at E-box sequences. More specific terms are already annotated with experimental evidence. Proposed replacements: E-box binding sequence-specific double-stranded DNA binding Supporting Evidence: PMID:28402879 it is well known that Ascl1 binds DNA as a homo- or heterodimer via its basic helix-loop-helix (bHLH) motif |
| GO:1990837 sequence-specific double-stranded DNA binding | IDA PMID:28473536 Impact of cytosine methylation on DNA binding specificities ... | ACCEPT | Summary: This high-throughput SELEX study characterized DNA binding specificities of human transcription factors including ASCL1. It confirms sequence-specific binding to E-box motifs. Reason: This is a core molecular function with direct experimental evidence. The SELEX method provides systematic characterization of DNA binding specificity. Supporting Evidence: PMID:28473536 By analysis of 542 human TFs with methylation-sensitive SELEX... we found that there are also many TFs that prefer CpG-methylated sequences |
| GO:0000785 chromatin | ISA GO_REF:0000113 | ACCEPT | Summary: ASCL1 binds chromatin as a pioneer transcription factor. This annotation from the TFClass database reflects ASCL1's chromatin association. Reason: ASCL1 associates with chromatin where it binds nucleosomal DNA and recruits chromatin remodelers. The pioneer factor activity (PMID:36931659) supports chromatin localization. Supporting Evidence: PMID:36931659 Pioneer transcription factors are thought to play pivotal roles in developmental processes by binding nucleosomal DNA |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | ISA GO_REF:0000113 | ACCEPT | Summary: This ISA annotation from TFClass is correct and consistent with ASCL1's function as a bHLH transcription factor regulating Pol II-dependent transcription. Reason: This is a core molecular function. Consistent with IBA annotation and experimental evidence. Supporting Evidence: PMID:10903890 The HASH-1/E2-2 complex binds an E-box (CACCTG) in vitro, and transactivates an E-box containing reporter construct in vivo. |
| GO:0045666 positive regulation of neuron differentiation | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation consistent with ASCL1's role as a proneural factor promoting neuronal differentiation. Reason: This is a core function with multiple supporting evidence types. The ISS is consistent with IBA and IEA annotations for the same term. Supporting Evidence: PMID:19008346 By overexpressing one of these, the transcription factor ASCL1, we were able to regain neurogenesis |
| GO:0030182 neuron differentiation | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for neuron differentiation, consistent with multiple other evidence types. Reason: Core function with abundant supporting evidence across multiple annotation types. Supporting Evidence: PMID:10903890 essential for proper development of olfactory and most peripheral autonomic neurons |
| GO:0048663 neuron fate commitment | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for neuron fate commitment, consistent with ASCL1's proneural function. Reason: Core function supported by multiple evidence types and extensive literature. Supporting Evidence: PMID:36931659 endogenous expression of ASCL1 drives progenitor differentiation |
| GO:0048665 neuron fate specification | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for neuron fate specification, consistent with ASCL1's role in specifying neuronal subtypes. Reason: Core function supported by experimental evidence for specific neuronal subtype specification. Supporting Evidence: PMID:12050665 One lineage expresses Dlx1/2 and Mash1 transcription factors, represents 65% of neocortical GABAergic neurons |
| GO:0048666 neuron development | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation for neuron development, consistent with ASCL1's essential role in neurogenesis. Reason: Core function supported by extensive literature and multiple evidence types. Supporting Evidence: PMID:10903890 essential for proper development of olfactory and most peripheral autonomic neurons |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:11736660 Proprotein convertase PACE4 is down-regulated by the basic h... | ACCEPT | Summary: ASCL1 represses PACE4 gene transcription via E-box binding. This demonstrates transcriptional repressor activity in addition to its better-known activator function. Reason: ASCL1 functions as both activator and repressor depending on target gene and context. The repression of PACE4 is directly demonstrated by this study. Supporting Evidence: PMID:11736660 The overexpression of hASH-1 or MASH-1 causes a marked decrease in endogenous PACE4 gene expression |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IDA PMID:11736660 Proprotein convertase PACE4 is down-regulated by the basic h... | ACCEPT | Summary: ASCL1 binds to the cis-regulatory E-box cluster in the PACE4 promoter to regulate transcription. Reason: This is a core molecular function with direct experimental evidence from gel shift assays demonstrating binding to the PACE4 promoter E-box cluster. Supporting Evidence: PMID:11736660 Binding of hASH-1 to the E-box cluster was confirmed by gel mobility-shift assay |
| GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific | IDA PMID:11736660 Proprotein convertase PACE4 is down-regulated by the basic h... | ACCEPT | Summary: ASCL1 functions as a transcriptional repressor of the PACE4 gene. This demonstrates context- dependent repressor activity. Reason: This is a documented molecular function of ASCL1. While primarily known as an activator, ASCL1 can repress specific target genes like PACE4 via E-box binding. Supporting Evidence: PMID:11736660 The overexpression of hASH-1 or MASH-1 causes a marked decrease in endogenous PACE4 gene expression |
| GO:0060579 ventral spinal cord interneuron fate commitment | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation consistent with ASCL1's role in V2b interneuron specification in spinal cord. Reason: Consistent with UniProt annotation describing ASCL1's function with FOXN4 in V2b specification. Supporting Evidence: UniProt:P50553 Acts synergistically with FOXN4 to specify the identity of V2b neurons |
| GO:0003358 noradrenergic neuron development | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation consistent with ASCL1's essential role in noradrenergic neuron development. Reason: Consistent with IMP evidence from PMID:14532329 demonstrating impaired noradrenergic development with ASCL1 mutations. Supporting Evidence: PMID:14532329 All HASH-1 mutant alleles impaired noradrenergic neuronal development |
| GO:0010468 regulation of gene expression | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ASCL1 regulates gene expression as a transcription factor. This is a very general term. Reason: While correct, this term is too general. More specific terms like "regulation of transcription by RNA polymerase II" are more informative and already annotated. Proposed replacements: regulation of transcription by RNA polymerase II |
| GO:0061549 sympathetic ganglion development | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation consistent with ASCL1's role in autonomic nervous system development. Reason: Consistent with ASCL1's essential role in peripheral autonomic neuron development. Supporting Evidence: PMID:10903890 essential for proper development of... most peripheral autonomic neurons |
| GO:0045892 negative regulation of DNA-templated transcription | IDA PMID:11736660 Proprotein convertase PACE4 is down-regulated by the basic h... | ACCEPT | Summary: ASCL1 negatively regulates transcription of the PACE4 gene. This is a more general term than the Pol II-specific repression annotation. Reason: This is demonstrated by the PACE4 repression study. Slightly more general than GO:0000122 but both are correct. Supporting Evidence: PMID:11736660 The overexpression of hASH-1 or MASH-1 causes a marked decrease in endogenous PACE4 gene expression |
| GO:0005634 nucleus | IDA PMID:12858003 Mechanisms of neuroendocrine differentiation in pulmonary ne... | ACCEPT | Summary: Nuclear localization demonstrated by immunohistochemistry in pulmonary neuroendocrine cells. Reason: Core cellular component annotation with direct experimental evidence. Supporting Evidence: PMID:12858003 Immunohistochemically, pulmonary neuroendocrine cells (PNECs) are positive for Mash1 |
| GO:0003359 noradrenergic neuron fate commitment | IMP PMID:14532329 Noradrenergic neuronal development is impaired by mutation o... | ACCEPT | Summary: HASH-1 mutations impair noradrenergic neuronal fate commitment, as shown by mutation analysis in CCHS patients and in vitro models. Reason: Core function with IMP evidence. Mutations in ASCL1 cause noradrenergic neuron development defects, demonstrating its essential role in fate commitment. Supporting Evidence: PMID:14532329 All HASH-1 mutant alleles impaired noradrenergic neuronal development, when overexpressed from adenoviral constructs. |
| GO:0021892 cerebral cortex GABAergic interneuron differentiation | IEP PMID:12050665 Origin of GABAergic neurons in the human neocortex. | ACCEPT | Summary: ASCL1 (Mash1) is expressed in progenitors that give rise to GABAergic interneurons in human neocortex, marking this specific lineage. Reason: This is a specific neuronal differentiation function supported by expression pattern analysis in human fetal cortex. Supporting Evidence: PMID:12050665 One lineage expresses Dlx1/2 and Mash1 transcription factors, represents 65% of neocortical GABAergic neurons in humans, and originates from Mash1-expressing progenitors |
| GO:0032526 response to retinoic acid | IEP PMID:12000752 Activation of the phosphatidylinositol 3-kinase/Akt signalin... | KEEP AS NON CORE | Summary: ASCL1 expression is rapidly reduced in response to retinoic acid treatment in neuroblastoma cells undergoing differentiation. Reason: ASCL1 expression responds to retinoic acid (downregulation), but this represents regulation OF ASCL1 rather than a primary function of ASCL1. Supporting Evidence: PMID:12000752 expression of neuroblast-specific ASCL1 (HASH-1) gene was promptly reduced after RA treatment |
| GO:0043425 bHLH transcription factor binding | IPI PMID:11940670 Notch signaling induces rapid degradation of achaete-scute h... | ACCEPT | Summary: ASCL1 interacts with E12, a bHLH transcription factor, and this interaction protects ASCL1 from Notch-induced degradation. Reason: This is a core molecular function. ASCL1 requires heterodimerization with bHLH E-proteins for DNA binding and stability. Supporting Evidence: PMID:11940670 Overexpression of the hASH1-dimerizing partner E12 could protect hASH1 from degradation |
| GO:0045665 negative regulation of neuron differentiation | IDA PMID:12000752 Activation of the phosphatidylinositol 3-kinase/Akt signalin... | REMOVE | Summary: This annotation seems inconsistent with ASCL1's primary role as a positive regulator of neuronal differentiation. The paper shows ASCL1 is downregulated during differentiation. Reason: The cited paper (PMID:12000752) shows that ASCL1 expression is reduced during RA-induced differentiation, not that ASCL1 negatively regulates differentiation. ASCL1 is a proneural factor that promotes differentiation. This annotation appears to be an error in interpretation. Supporting Evidence: PMID:12000752 expression of neuroblast-specific ASCL1 (HASH-1) gene was promptly reduced after RA treatment |
| GO:0060487 lung epithelial cell differentiation | NAS PMID:12858003 Mechanisms of neuroendocrine differentiation in pulmonary ne... | MODIFY | Summary: ASCL1 (hASH1) is specifically involved in neuroendocrine differentiation within lung epithelium, not general lung epithelial cell differentiation. Reason: ASCL1 is specifically required for pulmonary neuroendocrine cell differentiation, not general lung epithelial differentiation. A more specific term would be more accurate. Proposed replacements: lung neuroendocrine cell differentiation Supporting Evidence: PMID:12858003 Moreover, studies of small cell carcinoma and non- small cell carcinoma suggest that neuroendocrine differentiation could be regulated by hASH1 |
| GO:0070888 E-box binding | IDA PMID:11736660 Proprotein convertase PACE4 is down-regulated by the basic h... | ACCEPT | Summary: ASCL1 binds E-box sequences in the PACE4 promoter, confirmed by gel mobility-shift assay. Reason: This is a core molecular function with direct experimental evidence. Supporting Evidence: PMID:11736660 Binding of hASH-1 to the E-box cluster was confirmed by gel mobility-shift assay |
| GO:0003700 DNA-binding transcription factor activity | IDA PMID:10903890 HASH-1 and E2-2 are expressed in human neuroblastoma cells a... | ACCEPT | Summary: ASCL1 functions as a transcription factor, binding DNA and transactivating reporter genes. Reason: Core molecular function with direct experimental evidence from reporter assays. Supporting Evidence: PMID:10903890 The HASH-1/E2-2 complex binds an E-box (CACCTG) in vitro, and transactivates an E-box containing reporter construct in vivo |
| GO:0043425 bHLH transcription factor binding | IPI PMID:10903890 HASH-1 and E2-2 are expressed in human neuroblastoma cells a... | ACCEPT | Summary: ASCL1 interacts with E2-2 (TCF4), a bHLH transcription factor, demonstrated by yeast two-hybrid and co-immunoprecipitation. Reason: Core molecular function. Heterodimerization with E-proteins is essential for ASCL1 DNA binding and transcriptional activity. Supporting Evidence: PMID:10903890 E2-2 interacts with HASH-1 in both yeast and mammalian cells |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:10903890 HASH-1 and E2-2 are expressed in human neuroblastoma cells a... | ACCEPT | Summary: ASCL1 transactivates E-box containing reporter genes when complexed with E-proteins. Reason: Core function with direct experimental evidence from reporter assays. Supporting Evidence: PMID:10903890 transactivates an E-box containing reporter construct in vivo |
| GO:0048485 sympathetic nervous system development | NAS PMID:10903890 HASH-1 and E2-2 are expressed in human neuroblastoma cells a... | ACCEPT | Summary: ASCL1 is essential for development of peripheral autonomic neurons, which includes the sympathetic nervous system. Reason: This is a core biological process supported by the evidence for autonomic neuron development. Supporting Evidence: PMID:10903890 essential for proper development of... most peripheral autonomic neurons |
| GO:0070888 E-box binding | IDA PMID:10903890 HASH-1 and E2-2 are expressed in human neuroblastoma cells a... | ACCEPT | Summary: ASCL1/E2-2 complex binds E-box sequence (CACCTG) demonstrated by in vitro binding assays. Reason: Core molecular function with direct experimental evidence. Duplicate entry with different reference supporting the same function. Supporting Evidence: PMID:10903890 The HASH-1/E2-2 complex binds an E-box (CACCTG) in vitro |
| GO:0007219 Notch signaling pathway | IDA PMID:16160079 Conservation of the Notch1 signaling pathway in gastrointest... | ACCEPT | Summary: ASCL1 is regulated by and functions within the Notch signaling pathway. Notch1 activation represses ASCL1 expression. Reason: ASCL1 is a key component of the Notch signaling pathway, acting downstream of Notch (repressed by active Notch). It also activates DLL1/DLL3 which modulate Notch signaling. Supporting Evidence: PMID:16160079 Notch1 pathway activation led to an increase in hairy enhancer of split 1 (HES-1) protein and a concomitant silencing of human Notch1/HES-1/achaete-scute homolog 1 PMID:11940670 Notch signaling induces rapid degradation of achaete-scute homolog 1 |
| GO:0005634 nucleus | IDA PMID:17507989 Achaete-scute homolog-1 linked to remodeling and preneoplasi... | ACCEPT | Summary: Nuclear localization demonstrated by immunohistochemistry and functional studies. Reason: Core cellular component with direct experimental evidence. Multiple IDA entries support this. Supporting Evidence: PMID:17507989 Constitutive expression of human ASH-1 (hASH1) in mouse lung |
| GO:0005634 nucleus | IDA PMID:18311112 Human ASH1 expression in prostate cancer with neuroendocrine... | ACCEPT | Summary: Nuclear localization demonstrated by immunohistochemistry in prostate cancer cells with neuroendocrine differentiation. Reason: Core cellular component with direct experimental evidence. Supporting Evidence: PMID:18311112 Human ASH1 protein was analyzed by immunohistochemistry |
| GO:0022008 neurogenesis | IDA PMID:19008346 Regionally specified human neural progenitor cells derived f... | ACCEPT | Summary: ASCL1 overexpression increases neurogenesis in human neural progenitor cells. Reason: Core biological process with direct experimental evidence showing increased neuron production upon ASCL1 overexpression. Supporting Evidence: PMID:19008346 By overexpressing one of these, the transcription factor ASCL1, we were able to regain neurogenesis from hNPC(VM) cultures |
| GO:0043066 negative regulation of apoptotic process | IMP PMID:17507989 Achaete-scute homolog-1 linked to remodeling and preneoplasi... | KEEP AS NON CORE | Summary: ASCL1 expression confers resistance to apoptosis in lung epithelial cells. Knockdown increases apoptosis in lung cancer cells. Reason: This is a documented function of ASCL1 but represents a downstream effect rather than a primary function. It is relevant to ASCL1's role in cancer but not its core developmental neurogenesis function. Supporting Evidence: PMID:17507989 Knockdown of hASH1 gene in human lung cancer cells in vitro suppressed growth by increasing apoptosis. We also show that forced expression of hASH1 in immortalized human bronchial epithelial cells decreases apoptosis. |
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Q: What determines whether ASCL1 homodimerizes versus heterodimerizes with specific E-proteins?
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