HES1 (Hairy and Enhancer of Split 1) is a Class B basic helix-loop-helix (bHLH) transcriptional repressor of the HES/HEY family. It acts in the nucleus as a homodimer (or heterodimer with related bHLH-O proteins) that binds DNA preferentially at N-box motifs (5'-CACNAG-3') with high affinity and at E-box motifs (5'-CANNTG-3') with lower affinity, owing to a proline within its basic DNA-binding region. Repression depends on the bHLH and central Orange domain together with a C-terminal WRPW tetrapeptide that recruits Groucho/TLE corepressors and associated histone deacetylase activity (including SIRT1). HES1 is a principal effector of Notch signaling; ligand-activated Notch releases the Notch intracellular domain, which with RBPJ/CSL and MAML activates HES1 transcription. HES1 in turn represses proneural and tissue-specific bHLH activators (e.g., ASCL1/MASH1, the neurogenins, and E2A/ATOH targets). Through negative autoregulation at N-box elements in its own promoter, HES1 expression oscillates with ultradian (~2 hour) periodicity, and these dynamics help time progenitor maintenance versus differentiation. Biologically, HES1 maintains neural and other progenitor/stem-cell pools and blocks premature differentiation, and it is reused across many developmental contexts (nervous system, somitogenesis, inner ear, heart and great vessels, kidney, thymus, pancreas, and hematopoiesis).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000122 negative regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred negative regulation of Pol II transcription, the central biological-process role of HES1 as a Hairy/Enhancer-of-split repressor. Strongly supported by direct experimental data on autorepression and proneural-gene repression. Reason: This is a core function. HES1 is a transcriptional repressor that binds N-box elements and recruits Groucho/TLE corepressors; the IBA call across the HES/HEY clade matches direct human evidence. Supporting Evidence: PMID:7906273 it binds more preferentially to the N box (CACNAG) than to the E box (CANNTG) and acts as a negative regulator PMID:12535671 involved in HES1- and HEY2-mediated transcriptional repression |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that HES1 is a sequence-specific Pol II transcription factor. Accurate but generic; HES1 is specifically a repressor, captured more precisely by GO:0001227. Reason: Correct parent molecular-function term for a bHLH transcription factor. The more specific repressor activity term (GO:0001227) is also annotated and represents the precise function. Supporting Evidence: PMID:7906273 HES-1 binds to these sequences |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Nuclear localization inferred phylogenetically, consistent with HES1 acting as a DNA-binding nuclear transcription factor. Reason: HES1 is a transcription factor whose site of action is the nucleus; UniProt records Nucleus as the subcellular location. Supporting Evidence: file:human/HES1/HES1-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0007219 Notch signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: HES1 is a canonical downstream effector/target of Notch signaling, transcriptionally activated by the NICD-RBPJ/CSL-MAML complex. Phylogenetically well supported across the family. Reason: Acting as a transcriptional effector of Notch is a defining feature of HES1. Directly demonstrated in human cells where Notch1 activation increases HES1. Supporting Evidence: PMID:16160079 Notch1 pathway activation led to an increase in hairy enhancer of split 1 (HES-1) protein |
| GO:0009952 anterior/posterior pattern specification | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: A/P pattern specification is a developmental process attributed to the Hairy/HES family (e.g., segmentation clock in somitogenesis), downstream of HES1 repressor activity. Reason: This is a pleiotropic developmental output of HES1's repressor function rather than its core molecular role. HES1/Hes oscillations contribute to the segmentation clock and axial patterning. Supporting Evidence: file:human/HES1/HES1-deep-research-falcon.md HES1/Hes-family oscillators coordinate segmentation clock and neurogenic timing |
| GO:0045665 negative regulation of neuron differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: HES1 represses proneural genes to block neuronal differentiation and maintain progenitors; a well-supported, central neural function though it is one tissue-specific consequence of its repressor activity. Reason: This is the best-characterized biological consequence of HES1 repressor activity, but as a tissue/process-specific differentiation outcome it is non-core relative to the molecular repressor function. Strongly supported phylogenetically and experimentally. Supporting Evidence: PMID:19682396 inactivation of Notch-regulated genes such as Hes1 and Hes5 induced a premature neuronal differentiation during brain development |
| GO:0050767 regulation of neurogenesis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Regulation of neurogenesis is a broad neural-development process downstream of HES1 repressor activity; HES1 controls timing and progenitor maintenance during neurogenesis. Reason: Valid pleiotropic developmental role, parent of the negative regulation of neuron differentiation that HES1 executes; non-core relative to molecular function. Supporting Evidence: PMID:19682396 Notch signaling, which maintains stem cell characteristics of in-vivo-derived neuroprogenitors |
| GO:0070888 E-box binding | IBA GO_REF:0000033 | ACCEPT | Summary: HES1 binds E-box motifs (CANNTG), albeit with lower affinity than N-box. Phylogenetically supported and consistent with bHLH biology. Reason: HES1 binds E-box elements (low affinity) in addition to its preferred N-box; a genuine DNA-binding specificity of the protein. Supporting Evidence: file:human/HES1/HES1-uniprot.txt Binds DNA on N-box motifs 5'-CACNAG-3' with high affinity and on E-box motifs 5'-CANNTG-3' with low affinity |
| GO:0071820 N-box binding | IBA GO_REF:0000033 | ACCEPT | Summary: HES1 binds N-box motifs (CACNAG) with high affinity, its signature DNA recognition specificity, conferred by a helix-interrupting proline in the basic region. Reason: Core molecular function. N-box binding distinguishes HES1 from canonical E-box bHLH activators and underlies its autorepression. Supporting Evidence: PMID:7906273 it binds more preferentially to the N box (CACNAG) than to the E box (CANNTG) |
| GO:0003677 DNA binding | IEA GO_REF:0000120 | ACCEPT | Summary: Generic DNA binding inferred from the bHLH/Orange domain signature. Correct but subsumed by the more specific N-box/E-box and sequence-specific DNA binding terms. Reason: Accurate parent term for a DNA-binding transcription factor; the more informative children (N-box, E-box, sequence-specific dsDNA binding) are separately annotated. Supporting Evidence: PMID:7906273 HES-1 binds to these sequences |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: Nuclear localization predicted by electronic methods, consistent with experimentally determined nuclear location. Reason: HES1 is a nuclear transcription factor; UniProt records Nucleus as the subcellular location. Supporting Evidence: file:human/HES1/HES1-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: Broad transcription-regulation term assigned via InterPro (Orange domain). Correct but very general; HES1 acts specifically as a repressor. Reason: A correct high-level parent term consistent with HES1 function; more specific repressor terms are also present. Supporting Evidence: PMID:7906273 acts as a negative regulator |
| GO:0046983 protein dimerization activity | IEA GO_REF:0000002 | ACCEPT | Summary: Dimerization activity inferred from the HLH domain. HES1 functions as homo- and heterodimers via its helix-loop-helix, so this is accurate. Reason: The HLH domain mediates dimerization, a prerequisite for DNA binding; supported by the protein homodimerization annotations. Supporting Evidence: file:human/HES1/HES1-deep-research-falcon.md HES1 is a transcriptional repressor that binds DNA as homo- or heterodimers |
| GO:0005515 protein binding | IPI PMID:12535671 Human Sir2-related protein SIRT1 associates with the bHLH re... | MARK AS OVER ANNOTATED | Summary: Generic protein-binding annotation from the SIRT1 interaction. Uninformative as a bare term; the same interaction is better captured by histone deacetylase binding (GO:0042826). Reason: Bare protein binding is uninformative and discouraged. The underlying SIRT1 (a deacetylase) interaction is more usefully annotated as histone deacetylase binding, which is also present. Supporting Evidence: PMID:12535671 SIRT1, also physically associates with the human bHLH repressor proteins, hHES1 and hHEY2, both in vitro and in vivo |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | ACCEPT | Summary: Ortholog-projected negative regulation of Pol II transcription, matching the core repressor role and direct human evidence. Reason: Core function; duplicate of the IBA/IDA-supported repressor annotation. Supporting Evidence: PMID:12535671 involved in HES1- and HEY2-mediated transcriptional repression |
| GO:0000785 chromatin | IEA GO_REF:0000107 | ACCEPT | Summary: Localization to chromatin inferred by orthology, consistent with HES1 binding promoter/enhancer DNA and recruiting chromatin-modifying corepressors. Reason: A DNA-binding transcription factor that occupies target promoters is appropriately localized to chromatin. Supporting Evidence: PMID:7906273 DNase I foot-printing and gel mobility shift analyses show that HES-1 binds to these sequences |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: Ortholog-projected Pol II transcription factor activity; correct parent term, duplicate of the IBA annotation. Reason: Accurate; the repressor-specific child term GO:0001227 is the precise function and is also annotated. Supporting Evidence: PMID:7906273 HES-1 binds to these sequences |
| GO:0001217 DNA-binding transcription repressor activity | IEA GO_REF:0000107 | ACCEPT | Summary: HES1 is a sequence-specific DNA-binding transcriptional repressor; accurate molecular-function term (parent of the Pol II-specific GO:0001227). Reason: Core molecular function captured precisely. HES1 represses target promoters after DNA binding. Supporting Evidence: PMID:7906273 cotransfection of the HES-1 expression vector leads to approximately 40-fold repression in promoter activity |
| GO:0001222 transcription corepressor binding | IEA GO_REF:0000107 | ACCEPT | Summary: HES1 binds Groucho/TLE corepressors via its WRPW motif, so binding of a transcription corepressor is well supported. Reason: The C-terminal WRPW motif recruits TLE/Groucho corepressors, a defining mechanistic feature of HES1 repression. Supporting Evidence: file:human/HES1/HES1-uniprot.txt Interacts (via WPRW motif) with TLE1, and more weakly with TLE2 |
| GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific | IEA GO_REF:0000107 | ACCEPT | Summary: The precise molecular function of HES1: a Pol II-specific sequence-specific DNA-binding transcriptional repressor. Strongly supported by direct repression assays. Reason: This is HES1's core molecular function, capturing both DNA-binding and repressor activity at the right level of specificity. Supporting Evidence: PMID:7906273 cotransfection of the HES-1 expression vector leads to approximately 40-fold repression in promoter activity |
| GO:0003143 embryonic heart tube morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Developmental role in cardiac morphogenesis projected from ortholog phenotypes; a tissue-specific downstream effect of HES1 repressor activity. Reason: Plausible pleiotropic developmental role (HES1 functions in cardiovascular development) but peripheral to the core molecular function. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:embryonic heart tube morphogenesis |
| GO:0003281 ventricular septum development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Cardiac septation role projected by orthology; pleiotropic developmental output downstream of HES1. Reason: Tissue-specific developmental process, non-core relative to molecular function. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:ventricular septum development |
| GO:0003682 chromatin binding | IEA GO_REF:0000107 | ACCEPT | Summary: Chromatin binding consistent with a promoter-occupying transcription factor; accurate but generic relative to sequence-specific DNA binding. Reason: HES1 occupies target chromatin; consistent with its DNA-binding activity. Supporting Evidence: PMID:7906273 HES-1 binds to these sequences |
| GO:0005737 cytoplasm | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Cytoplasmic localization projected from orthologs. HES1 is characterized as a nuclear transcription factor; cytoplasmic presence is not well supported for the human protein and may reflect shuttling/degradation pools. Reason: The experimentally established site of action is the nucleus (UniProt: Nucleus). Cytoplasmic annotation is not the functional location and likely over-annotated from ortholog projection. Supporting Evidence: file:human/HES1/HES1-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0008432 JUN kinase binding | IEA GO_REF:0000107 | UNDECIDED | Summary: JNK binding projected from an ortholog; not supported by direct human evidence and not a recognized core activity of HES1. Reason: This electronic ortholog projection cannot be verified against accessible human literature; no primary evidence for a HES1-JNK interaction is available here. Supporting Evidence: file:human/HES1/HES1-uniprot.txt F:JUN kinase binding; IEA:Ensembl |
| GO:0010628 positive regulation of gene expression | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Broad positive-regulation term projected from orthologs. HES1 is predominantly a repressor; positive effects are typically indirect (de-repression of other repressors) and this generic term adds little. Reason: HES1's direct molecular activity is repression. Generic positive regulation of gene expression is at best an indirect, non-core effect and conflicts with the well-established repressor role. Supporting Evidence: PMID:7906273 acts as a negative regulator |
| GO:0010629 negative regulation of gene expression | IEA GO_REF:0000107 | ACCEPT | Summary: Negative regulation of gene expression, consistent with HES1's repressor function (a parent of the Pol II repression term). Reason: Accurate process term reflecting HES1 repression of target genes. Supporting Evidence: PMID:7906273 acts as a negative regulator |
| GO:0010977 negative regulation of neuron projection development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Neuron projection (neurite) suppression projected from orthologs; a neural-differentiation-related downstream effect of HES1 repression. Reason: Plausible neural developmental role consistent with HES1 inhibiting neuronal differentiation, but tissue-specific and non-core. Supporting Evidence: PMID:8020957 can, like that in Drosophila, suppress neuronal differentiation events |
| GO:0016363 nuclear matrix | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Nuclear matrix localization projected from orthologs; a subnuclear compartment consistent with nuclear function but not specifically characterized for human HES1. Reason: Consistent with nuclear localization but a more specific subnuclear claim without direct human support; nucleus/nucleoplasm are the well-supported locations. Supporting Evidence: file:human/HES1/HES1-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0021861 forebrain radial glial cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: HES1 maintains radial glia/neural progenitors in the forebrain, delaying neuronal differentiation; tissue-specific developmental role. Reason: Well-aligned with HES1 progenitor-maintenance function but a tissue-specific developmental process, hence non-core. Supporting Evidence: PMID:19682396 maintain stem cell characteristics mainly through Notch signaling |
| GO:0030182 neuron differentiation | IEA GO_REF:0000107 | MODIFY | Summary: Generic neuron differentiation process projected from orthologs. HES1 specifically acts to negatively regulate neuronal differentiation, captured better by GO:0045665. Reason: HES1 inhibits rather than promotes neuron differentiation; the bare neuron differentiation term loses directionality. Replace with the negative regulation term already supported. Proposed replacements: negative regulation of neuron differentiation Supporting Evidence: PMID:19682396 inactivation of Notch-regulated genes such as Hes1 and Hes5 induced a premature neuronal differentiation |
| GO:0032991 protein-containing complex | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Generic complex membership projected from orthologs. HES1 acts in repressor complexes (with TLE/Groucho, HDAC/SIRT1) and as dimers, but this root-level cellular-component term is uninformative. Reason: Root-level protein-containing complex carries no specific information; the meaningful complex relationships are captured by corepressor/dimerization annotations. Supporting Evidence: file:human/HES1/HES1-uniprot.txt Transcription repression requires formation of a complex with a corepressor protein of the Groucho/TLE family |
| GO:0035315 hair cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Inner-ear hair cell differentiation role projected from orthologs; HES1 negatively regulates auditory hair-cell fate, a tissue-specific developmental output. Reason: Valid pleiotropic developmental role in the inner ear, non-core relative to molecular function. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:hair cell differentiation |
| GO:0035909 aorta morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Aortic morphogenesis role projected from orthologs; cardiovascular developmental process downstream of HES1. Reason: Pleiotropic cardiovascular developmental role; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:aorta morphogenesis |
| GO:0035910 ascending aorta morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ascending-aorta morphogenesis projected from orthologs; tissue-specific cardiovascular developmental process. Reason: Pleiotropic cardiovascular developmental role; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:ascending aorta morphogenesis |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | ACCEPT | Summary: Identical-protein binding reflects HES1 homodimerization. Accurate, but the more informative homodimerization activity term is also annotated. Reason: HES1 forms homodimers via its HLH domain; identical protein binding is consistent with this. Supporting Evidence: file:human/HES1/HES1-deep-research-falcon.md HES1 is a transcriptional repressor that binds DNA as homo- or heterodimers |
| GO:0042803 protein homodimerization activity | IEA GO_REF:0000107 | ACCEPT | Summary: HES1 homodimerizes through its helix-loop-helix domain to bind DNA; well supported molecular function. Reason: Homodimerization is a prerequisite for DNA binding by bHLH proteins and is documented for HES1. Supporting Evidence: file:human/HES1/HES1-deep-research-falcon.md HES1 is a transcriptional repressor that binds DNA as homo- or heterodimers |
| GO:0043254 regulation of protein-containing complex assembly | IEA GO_REF:0000107 | UNDECIDED | Summary: Regulation of complex assembly projected from orthologs; not a well-characterized direct function of human HES1 and only loosely related to its repressor-complex role. Reason: This electronic projection lacks accessible primary support for human HES1; cannot be confirmed or refuted from available evidence. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:regulation of protein-containing complex assembly |
| GO:0043279 response to alkaloid | IEA GO_REF:0000107 | UNDECIDED | Summary: Response to alkaloid projected from a rodent ortholog (likely a pharmacological treatment phenotype); not a core or human-validated function. Reason: Generic chemical-response term from ortholog projection without accessible human evidence; cannot be verified. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:response to alkaloid; IEA:Ensembl |
| GO:0043398 HLH domain binding | IEA GO_REF:0000107 | ACCEPT | Summary: Binding to other HLH-domain proteins is consistent with HES1 heterodimerization with bHLH partners (e.g., HES6) and sequestration of proneural bHLH factors. Reason: HES1 interacts with HLH-domain proteins through its own HLH domain (heterodimerization / sequestration of bHLH activators). Supporting Evidence: file:human/HES1/HES1-uniprot.txt Interacts with HES6 |
| GO:0043565 sequence-specific DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: Sequence-specific DNA binding, consistent with HES1's recognition of N-box and E-box motifs. Reason: HES1 binds defined DNA sequence motifs; accurate parent of the N-box/E-box terms. Supporting Evidence: PMID:7906273 it binds more preferentially to the N box (CACNAG) |
| GO:0044877 protein-containing complex binding | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Generic complex-binding term projected from orthologs. HES1 binds the Groucho/TLE corepressor and FA core complex, but this root-level term is uninformative. Reason: Uninformative high-level binding term; specific interactions (corepressor binding, HDAC binding) capture the meaningful biology. Supporting Evidence: file:human/HES1/HES1-uniprot.txt Interacts with an FA complex, composed of FANCA, FANCF, FANCG and FANCL |
| GO:0045687 positive regulation of glial cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: By delaying neuronal differentiation, HES1 biases progenitors toward later glial fates; this positive glial role is projected from orthologs and is a tissue-specific developmental effect. Reason: Plausible developmental consequence of HES1 maintaining progenitors long enough to permit gliogenesis; non-core and tissue-specific. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:positive regulation of astrocyte differentiation |
| GO:0045747 positive regulation of Notch signaling pathway | IEA GO_REF:0000107 | UNDECIDED | Summary: Positive regulation of Notch signaling projected from orthologs. HES1 is mainly a downstream effector of Notch; a feed-forward positive effect on the pathway is not a well-established core function. Reason: Direction and mechanism of HES1 feedback on Notch signaling are context-dependent and not clearly supported by accessible human evidence; HES1 is primarily an effector, not a pathway activator. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:positive regulation of Notch signaling pathway |
| GO:0045892 negative regulation of DNA-templated transcription | IEA GO_REF:0000120 | ACCEPT | Summary: Negative regulation of DNA-templated transcription, the general biological-process expression of HES1's repressor activity. Directly supported in human cells. Reason: Core repressor function; consistent with direct repression assays and the SIRT1 study. Supporting Evidence: PMID:12535671 involved in HES1- and HEY2-mediated transcriptional repression |
| GO:0045893 positive regulation of DNA-templated transcription | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Positive regulation of DNA-templated transcription projected from orthologs. Conflicts with HES1's established role as a repressor; any activation is indirect. Reason: HES1's direct molecular activity is repression; a generic positive transcription regulation term is an indirect, non-core effect that misrepresents the core function. Supporting Evidence: PMID:7906273 acts as a negative regulator |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Positive regulation of Pol II transcription projected from orthologs; contradicts the predominant repressor role of HES1. Reason: HES1 acts as a Pol II repressor; positive Pol II regulation is at most indirect (de-repression) and conflicts with its core function. Supporting Evidence: PMID:7906273 acts as a negative regulator |
| GO:0045977 positive regulation of mitotic cell cycle, embryonic | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: HES1 promotes proliferation/cell-cycle progression of embryonic progenitors (consistent with progenitor maintenance); projected from orthologs. Reason: Consistent with HES1 keeping progenitors proliferative, but a tissue/stage-specific developmental output rather than the core molecular function. Supporting Evidence: PMID:19682396 proliferation potential in the NESs |
| GO:0046425 regulation of receptor signaling pathway via JAK-STAT | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Regulation of JAK-STAT signaling projected from orthologs; HES1 can promote STAT3 phosphorylation in some contexts, a cross-talk role rather than a core function. Reason: Context-dependent signaling cross-talk (HES1-STAT3/JAK axis) is reported but peripheral to the core repressor function. Supporting Evidence: file:human/HES1/HES1-deep-research-falcon.md HES1 can bind STAT3 and facilitate its phosphorylation via JAK2 |
| GO:0046427 positive regulation of receptor signaling pathway via JAK-STAT | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of JAK-STAT signaling projected from orthologs; aligns with reported HES1 promotion of STAT3 phosphorylation. Reason: Reported signaling cross-talk role, non-core relative to molecular function. Supporting Evidence: file:human/HES1/HES1-deep-research-falcon.md HES1 can bind STAT3 and facilitate its phosphorylation via JAK2 |
| GO:0048538 thymus development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Thymus development role projected from orthologs; HES1 functions downstream of Notch in T-lineage/thymic development. Reason: Pleiotropic immune/developmental role consistent with Notch-HES1 function in the thymus; non-core. Supporting Evidence: PMID:12032823 its interference with lymphoid B and myeloid maturation is partly mediated by Hes1 and Hes5 |
| GO:0048711 positive regulation of astrocyte differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Positive regulation of astrocyte (glial) differentiation, a developmental consequence of HES1 delaying neurogenesis; projected from orthologs. Reason: Tissue-specific developmental role consistent with HES1 promoting gliogenesis at the expense of neurogenesis; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:positive regulation of astrocyte differentiation |
| GO:0048715 negative regulation of oligodendrocyte differentiation | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Negative regulation of oligodendrocyte differentiation, consistent with HES1 repression of differentiation programs; projected electronically. Reason: Tissue-specific glial developmental role downstream of HES1 repressor activity; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:negative regulation of oligodendrocyte differentiation |
| GO:0048844 artery morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Artery morphogenesis role projected from orthologs; cardiovascular developmental process downstream of HES1/Notch. Reason: Pleiotropic vascular developmental role; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:artery morphogenesis |
| GO:0050768 negative regulation of neurogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Negative regulation of neurogenesis, a central neural role of HES1 (suppressing proneural genes to maintain progenitors); projected electronically. Reason: Well-supported neural developmental role consistent with HES1 function, but a process-level output, hence non-core. Supporting Evidence: PMID:8020957 can, like that in Drosophila, suppress neuronal differentiation events |
| GO:0051087 protein-folding chaperone binding | IEA GO_REF:0000107 | UNDECIDED | Summary: Chaperone binding projected from an ortholog; not supported by accessible human evidence and not a recognized HES1 function. Reason: Electronic ortholog projection without verifiable human support; cannot confirm or refute. Supporting Evidence: file:human/HES1/HES1-uniprot.txt F:protein-folding chaperone binding; IEA:Ensembl |
| GO:0060253 negative regulation of glial cell proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Negative regulation of glial cell proliferation projected from orthologs; a tissue-specific developmental role. Reason: Plausible context-specific role downstream of HES1; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:negative regulation of glial cell proliferation |
| GO:0060412 ventricular septum morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Cardiac septum morphogenesis projected from orthologs; cardiovascular developmental output of HES1. Reason: Pleiotropic cardiovascular developmental role; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:ventricular septum morphogenesis |
| GO:0060675 ureteric bud morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ureteric bud morphogenesis projected from orthologs; HES1 has documented roles in kidney development. Reason: Pleiotropic renal developmental role; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:ureteric bud morphogenesis |
| GO:0060716 labyrinthine layer blood vessel development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Placental labyrinth vascular development projected from orthologs; tissue-specific developmental process. Reason: Pleiotropic placental/vascular developmental role; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:labyrinthine layer blood vessel development |
| GO:0061626 pharyngeal arch artery morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Pharyngeal arch artery morphogenesis projected from orthologs; cardiovascular developmental process. Reason: Pleiotropic cardiovascular developmental role; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:pharyngeal arch artery morphogenesis |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | IEA GO_REF:0000107 | ACCEPT | Summary: Binding to Pol II transcription factors, consistent with HES1 sequestering/repressing proneural bHLH activators (e.g., interfering with E2A/E47 and MYOD1). Reason: HES1 binds and antagonizes other Pol II transcription factors (E-proteins, MYOD1), a documented mechanism of its repressor action. Supporting Evidence: PMID:12032823 their ability to interfere with the transcriptional activity of E2A in a reporter assay |
| GO:0065003 protein-containing complex assembly | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Generic complex-assembly process projected from orthologs. HES1 nucleates repressor complexes and supports FA core complex stability, but this broad term is uninformative. Reason: Very general process term; specific complex relationships (corepressor recruitment, FA core complex) are captured elsewhere. Supporting Evidence: file:human/HES1/HES1-uniprot.txt required for the stability and nuclear localization of FA core complex proteins |
| GO:0070888 E-box binding | IEA GO_REF:0000120 | ACCEPT | Summary: E-box binding (electronic), duplicate of the IBA/ISS annotations; HES1 binds E-box with lower affinity than N-box. Reason: Genuine low-affinity DNA-binding specificity of HES1. Supporting Evidence: file:human/HES1/HES1-uniprot.txt on E-box motifs 5'-CANNTG-3' with low affinity |
| GO:0071347 cellular response to interleukin-1 | IEA GO_REF:0000107 | UNDECIDED | Summary: Response to IL-1 projected from a rodent ortholog; an inducible expression/response phenotype rather than a core function. Reason: Electronic ortholog projection of a stimulus-response phenotype without accessible human support; cannot verify. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:cellular response to interleukin-1 |
| GO:0071356 cellular response to tumor necrosis factor | IEA GO_REF:0000107 | UNDECIDED | Summary: Response to TNF projected from a rodent ortholog; inducible response phenotype rather than a core function. Reason: Electronic ortholog projection without verifiable human support. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:cellular response to tumor necrosis factor |
| GO:0071398 cellular response to fatty acid | IEA GO_REF:0000107 | UNDECIDED | Summary: Response to fatty acid projected from a rodent ortholog; inducible response phenotype, not a core function. Reason: Electronic ortholog projection without verifiable human support. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:cellular response to fatty acid |
| GO:0071820 N-box binding | IEA GO_REF:0000120 | ACCEPT | Summary: N-box binding (electronic), duplicate of the IBA/ISS annotations; the signature high-affinity DNA recognition of HES1. Reason: Core DNA-binding specificity of HES1. Supporting Evidence: PMID:7906273 it binds more preferentially to the N box (CACNAG) |
| GO:0072012 glomerulus vasculature development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Glomerular vasculature development projected from orthologs; renal/vascular developmental process. Reason: Pleiotropic renal developmental role; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:glomerulus vasculature development |
| GO:0072049 comma-shaped body morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Comma-shaped body morphogenesis (nephron development) projected from orthologs; renal developmental process. Reason: Pleiotropic renal developmental role; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:comma-shaped body morphogenesis |
| GO:0072050 S-shaped body morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: S-shaped body morphogenesis (nephron development) projected from orthologs; renal developmental process. Reason: Pleiotropic renal developmental role; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:S-shaped body morphogenesis |
| GO:0072141 renal interstitial fibroblast development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Renal interstitial fibroblast development projected from orthologs; kidney developmental process. Reason: Pleiotropic renal developmental role; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:renal interstitial fibroblast development |
| GO:0072282 metanephric nephron tubule morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Metanephric nephron tubule morphogenesis projected from orthologs; kidney developmental process. Reason: Pleiotropic renal developmental role; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:metanephric nephron tubule morphogenesis |
| GO:0090281 negative regulation of calcium ion import | IEA GO_REF:0000107 | UNDECIDED | Summary: Negative regulation of calcium import projected from a rodent ortholog; not a recognized core function and not supported by accessible human evidence. Reason: Electronic ortholog projection of a specialized phenotype without verifiable human support. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:negative regulation of calcium ion import |
| GO:0097066 response to thyroid hormone | IEA GO_REF:0000107 | UNDECIDED | Summary: Response to thyroid hormone projected from a rodent ortholog; an inducible-response phenotype, not a core function. Reason: Electronic ortholog projection without verifiable human support. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:response to thyroid hormone |
| GO:0097084 vascular associated smooth muscle cell development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Vascular smooth muscle cell development projected from orthologs; cardiovascular developmental process downstream of HES1/Notch. Reason: Pleiotropic vascular developmental role; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:vascular associated smooth muscle cell development |
| GO:0097150 neuronal stem cell population maintenance | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Maintenance of the neural stem-cell pool, a hallmark HES1 role (electronic duplicate of the IEP annotation from PMID:19682396). Reason: Central neural-progenitor role of HES1, but a process-level developmental output; non-core relative to molecular function. Supporting Evidence: PMID:19682396 maintain stem cell characteristics mainly through Notch signaling |
| GO:1904010 response to Aroclor 1254 | IEA GO_REF:0000107 | UNDECIDED | Summary: Response to the PCB mixture Aroclor 1254, projected from a rodent ortholog; a toxicological treatment phenotype, not a core function. Reason: Highly specific chemical-response phenotype from ortholog projection without verifiable human support. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:response to Aroclor 1254 |
| GO:1990090 cellular response to nerve growth factor stimulus | IEA GO_REF:0000107 | UNDECIDED | Summary: Response to NGF projected from a rodent ortholog; consistent with HES1/RHL acting as an immediate-early gene responsive to growth factors, but not verified for human. Reason: Ortholog projection of a growth-factor response phenotype without verifiable human support. Supporting Evidence: PMID:8020957 behaves as an immediate-early gene in its response to growth factors |
| GO:2000978 negative regulation of forebrain neuron differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Negative regulation of forebrain neuron differentiation, a specific neural role of HES1 in maintaining forebrain progenitors; electronic duplicate of the ISS annotation. Reason: Tissue-specific neural developmental role consistent with HES1 repression of neuronal differentiation; non-core. Supporting Evidence: PMID:19682396 inactivation of Notch-regulated genes such as Hes1 and Hes5 induced a premature neuronal differentiation |
| GO:2000981 negative regulation of inner ear receptor cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Negative regulation of inner ear receptor cell (hair cell) differentiation projected from orthologs; tissue-specific developmental role. Reason: Pleiotropic inner-ear developmental role downstream of HES1 repressor activity; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:negative regulation of inner ear auditory receptor cell differentiation |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (Human Protein Atlas) localizes HES1 to the nucleoplasm, consistent with its role as a nuclear transcription factor. Reason: Experimental localization supporting the nuclear/nucleoplasmic site of action. Supporting Evidence: file:human/HES1/HES1-uniprot.txt C:nucleoplasm; IDA:HPA |
| GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity-based assignment of the precise repressor activity, transferred from mouse Hes1 (P35428). Matches direct human repression data. Reason: Core molecular function; well supported and consistent with the IEA and experimental evidence. Supporting Evidence: PMID:7906273 cotransfection of the HES-1 expression vector leads to approximately 40-fold repression in promoter activity |
| GO:1990837 sequence-specific double-stranded DNA binding | IDA PMID:28473536 Impact of cytosine methylation on DNA binding specificities ... | ACCEPT | Summary: HES1 binding to specific double-stranded DNA was assayed directly by methylation-sensitive SELEX in a genome-scale study of human transcription-factor binding specificities. Reason: Direct experimental demonstration of sequence-specific dsDNA binding by human HES1 (SELEX), supporting its DNA-binding function. Supporting Evidence: PMID:28473536 systematic analysis of DNA binding specificities of full-length TFs and eDBDs using unmethylated and CpG-methylated DNA ligands |
| GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding | ISS GO_REF:0000024 | ACCEPT | Summary: Binding to Pol II transcription factors transferred by similarity from mouse Hes1; consistent with HES1 antagonizing E-proteins/proneural bHLH activators. Reason: HES1 binds and inhibits other Pol II transcription factors (E2A/E47, MYOD1); supported by reporter-assay interference data. Supporting Evidence: PMID:12032823 their ability to interfere with the transcriptional activity of E2A in a reporter assay |
| GO:0070888 E-box binding | ISS GO_REF:0000024 | ACCEPT | Summary: E-box binding transferred by similarity from mouse Hes1; low-affinity DNA-binding specificity of HES1. Reason: Genuine DNA-binding specificity; duplicate of IBA/IEA E-box annotations. Supporting Evidence: file:human/HES1/HES1-uniprot.txt on E-box motifs 5'-CANNTG-3' with low affinity |
| GO:0071820 N-box binding | ISS GO_REF:0000024 | ACCEPT | Summary: N-box binding transferred by similarity from mouse Hes1; the signature high-affinity DNA recognition of HES1. Reason: Core DNA-binding specificity; duplicate of IBA/IEA N-box annotations. Supporting Evidence: PMID:7906273 it binds more preferentially to the N box (CACNAG) |
| GO:0061626 pharyngeal arch artery morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Pharyngeal arch artery morphogenesis transferred by similarity from mouse Hes1; cardiovascular developmental process. Reason: Pleiotropic cardiovascular developmental role; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:pharyngeal arch artery morphogenesis |
| GO:0003143 embryonic heart tube morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Embryonic heart tube morphogenesis transferred by similarity from mouse Hes1; cardiovascular developmental process. Reason: Pleiotropic cardiovascular developmental role; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:embryonic heart tube morphogenesis |
| GO:0035910 ascending aorta morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ascending aorta morphogenesis transferred by similarity from mouse Hes1; cardiovascular developmental process. Reason: Pleiotropic cardiovascular developmental role; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:ascending aorta morphogenesis |
| GO:0045977 positive regulation of mitotic cell cycle, embryonic | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of embryonic mitotic cell cycle transferred by similarity; consistent with HES1 keeping progenitors proliferative. Reason: Tissue/stage-specific proliferative role; non-core relative to molecular function. Supporting Evidence: PMID:19682396 proliferation potential in the NESs |
| GO:0060412 ventricular septum morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ventricular septum morphogenesis transferred by similarity from mouse Hes1; cardiovascular developmental process. Reason: Pleiotropic cardiovascular developmental role; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:ventricular septum morphogenesis |
| GO:2000978 negative regulation of forebrain neuron differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Negative regulation of forebrain neuron differentiation transferred by similarity; a specific neural role of HES1. Reason: Tissue-specific neural developmental role; non-core. Supporting Evidence: PMID:19682396 inactivation of Notch-regulated genes such as Hes1 and Hes5 induced a premature neuronal differentiation |
| GO:0097150 neuronal stem cell population maintenance | IEP PMID:19682396 Notch signaling is required for maintaining stem-cell featur... | KEEP AS NON CORE | Summary: Expression-based evidence (IEP) that HES1, induced by Notch in human hESC-derived neuroprogenitors, correlates with maintenance of neural stem-cell features; inhibition of Notch reduces NSC markers and triggers neuronal differentiation. Reason: Central neural-progenitor maintenance role of HES1, supported by human expression/perturbation data, but a process-level output and non-core relative to molecular function. Supporting Evidence: PMID:19682396 Notch signaling, which maintains stem cell characteristics of in-vivo-derived neuroprogenitors, is active in these hESC-derived NESs |
| GO:0007219 Notch signaling pathway | IMP PMID:19682396 Notch signaling is required for maintaining stem-cell featur... | ACCEPT | Summary: Mutant/perturbation phenotype (gamma-secretase inhibition of Notch) in human neuroprogenitors implicates HES1 as a Notch-pathway effector controlling stem-cell features. Reason: HES1 acting in the Notch signaling pathway is a defining feature, supported here by perturbation of Notch in human cells. Supporting Evidence: PMID:19682396 Inhibition of the Notch signaling by a gamma-secretase inhibitor reduced rosette structures, expression levels of NSC marker genes and proliferation potential |
| GO:0021861 forebrain radial glial cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Forebrain radial glial cell differentiation transferred by similarity; HES1 maintains radial glia/neural progenitors. Reason: Tissue-specific neural developmental role; non-core. Supporting Evidence: PMID:19682396 maintain stem cell characteristics mainly through Notch signaling |
| GO:0042531 positive regulation of tyrosine phosphorylation of STAT protein | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of STAT tyrosine phosphorylation transferred by similarity; aligns with reported HES1 promotion of STAT3 phosphorylation via JAK2. Reason: Context-dependent signaling cross-talk role, peripheral to the core repressor function. Supporting Evidence: file:human/HES1/HES1-deep-research-falcon.md HES1 can bind STAT3 and facilitate its phosphorylation via JAK2 |
| GO:0043388 positive regulation of DNA binding | ISS GO_REF:0000024 | UNDECIDED | Summary: Positive regulation of DNA binding transferred by similarity from mouse Hes1; mechanism for the human protein is not clearly defined. Reason: The biological meaning of this ISS-transferred term for human HES1 is unclear and not supported by accessible primary evidence. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:positive regulation of DNA binding |
| GO:0043565 sequence-specific DNA binding | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-specific DNA binding transferred by similarity; consistent with HES1 recognition of N-box/E-box motifs. Reason: Accurate DNA-binding term; duplicate of the IEA and IDA support. Supporting Evidence: PMID:7906273 it binds more preferentially to the N box (CACNAG) |
| GO:0046425 regulation of receptor signaling pathway via JAK-STAT | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Regulation of JAK-STAT signaling transferred by similarity; HES1 cross-talk with STAT3/JAK is reported. Reason: Context-dependent signaling cross-talk, non-core. Supporting Evidence: file:human/HES1/HES1-deep-research-falcon.md HES1 can bind STAT3 and facilitate its phosphorylation via JAK2 |
| GO:0046427 positive regulation of receptor signaling pathway via JAK-STAT | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of JAK-STAT signaling transferred by similarity; aligns with reported HES1 promotion of STAT3 phosphorylation. Reason: Context-dependent signaling cross-talk, non-core. Supporting Evidence: file:human/HES1/HES1-deep-research-falcon.md HES1 can bind STAT3 and facilitate its phosphorylation via JAK2 |
| GO:0065003 protein-containing complex assembly | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Generic complex-assembly process transferred by similarity; HES1 contributes to repressor and FA core complex assembly/stability but the broad term is uninformative. Reason: Very general process term; meaningful complex relationships are captured by specific corepressor/FA-complex annotations. Supporting Evidence: file:human/HES1/HES1-uniprot.txt required for the stability and nuclear localization of FA core complex proteins |
| GO:2000737 negative regulation of stem cell differentiation | IMP PMID:19682396 Notch signaling is required for maintaining stem-cell featur... | KEEP AS NON CORE | Summary: Perturbation evidence that HES1 (downstream of Notch) suppresses differentiation of human neural stem cells, maintaining the progenitor state. Reason: Well-supported stem-cell maintenance role, but a process-level developmental output; non-core relative to molecular function. Supporting Evidence: PMID:19682396 if combined with withdrawal of growth factors, triggered differentiation toward neurons |
| GO:2000974 negative regulation of pro-B cell differentiation | IMP PMID:12032823 Overexpression of the Notch target genes Hes in vivo induces... | KEEP AS NON CORE | Summary: Overexpression of Hes1 in vivo impaired B-cell (pro-B) differentiation, partly via interference with E2A activity, demonstrating a role in suppressing B-lineage differentiation. Reason: Genuine experimentally supported hematopoietic role downstream of HES1 repressor activity, but tissue-specific and non-core. Supporting Evidence: PMID:12032823 cells transduced with Hes1 or Hes5 were partially impaired in their ability to differentiate into B cells |
| GO:0042803 protein homodimerization activity | ISS GO_REF:0000024 | ACCEPT | Summary: Homodimerization activity transferred by similarity from mouse Hes1; HES1 binds DNA as a homodimer via its HLH domain. Reason: Homodimerization is required for bHLH DNA binding; duplicate of the IEA annotation. Supporting Evidence: file:human/HES1/HES1-deep-research-falcon.md HES1 is a transcriptional repressor that binds DNA as homo- or heterodimers |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:12032823 Overexpression of the Notch target genes Hes in vivo induces... | ACCEPT | Summary: Direct assay evidence that HES1 represses transcription, shown by interference with E2A transcriptional activity in a reporter assay. Reason: Core repressor function with direct experimental support. Supporting Evidence: PMID:12032823 their ability to interfere with the transcriptional activity of E2A in a reporter assay was comparable to that of Notch1IC |
| GO:0005634 nucleus | ISS GO_REF:0000024 | ACCEPT | Summary: Nuclear localization transferred by similarity from mouse Hes1; consistent with experimentally determined nuclear location. Reason: HES1 acts in the nucleus; duplicate of IBA/IEA nucleus annotations. Supporting Evidence: file:human/HES1/HES1-uniprot.txt SUBCELLULAR LOCATION: Nucleus |
| GO:0048711 positive regulation of astrocyte differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of astrocyte differentiation transferred by similarity; developmental consequence of HES1 delaying neurogenesis. Reason: Tissue-specific developmental role; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:positive regulation of astrocyte differentiation |
| GO:0048715 negative regulation of oligodendrocyte differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Negative regulation of oligodendrocyte differentiation transferred by similarity; consistent with HES1 repression of differentiation. Reason: Tissue-specific glial developmental role; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:negative regulation of oligodendrocyte differentiation |
| GO:0060253 negative regulation of glial cell proliferation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Negative regulation of glial cell proliferation transferred by similarity; tissue-specific developmental role. Reason: Context-specific role downstream of HES1; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:negative regulation of glial cell proliferation |
| GO:0003151 outflow tract morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Cardiac outflow tract morphogenesis transferred by similarity from mouse Hes1; cardiovascular developmental process. Reason: Pleiotropic cardiovascular developmental role; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:outflow tract morphogenesis |
| GO:0003281 ventricular septum development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ventricular septum development transferred by similarity from mouse Hes1; cardiovascular developmental process. Reason: Pleiotropic cardiovascular developmental role; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:ventricular septum development |
| GO:0008284 positive regulation of cell population proliferation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Positive regulation of cell proliferation transferred by similarity; consistent with HES1 maintaining proliferative progenitors, though direction is context-dependent. Reason: HES1 promotes progenitor proliferation in many contexts (and restrains it in others); a context-dependent developmental output, non-core. Supporting Evidence: PMID:19682396 proliferation potential in the NESs |
| GO:0045944 positive regulation of transcription by RNA polymerase II | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Positive regulation of Pol II transcription transferred by similarity; contradicts the predominant repressor role of HES1. Reason: HES1 is a Pol II repressor; positive Pol II regulation is at most indirect and conflicts with the core function. Supporting Evidence: PMID:7906273 acts as a negative regulator |
| GO:0048538 thymus development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Thymus development transferred by similarity from mouse Hes1; immune/developmental role downstream of Notch-HES1. Reason: Pleiotropic immune/developmental role; non-core. Supporting Evidence: PMID:12032823 its interference with lymphoid B and myeloid maturation is partly mediated by Hes1 and Hes5 |
| GO:0048844 artery morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Artery morphogenesis transferred by similarity from mouse Hes1; cardiovascular developmental process. Reason: Pleiotropic cardiovascular developmental role; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:artery morphogenesis |
| GO:0097084 vascular associated smooth muscle cell development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Vascular smooth muscle cell development transferred by similarity from mouse Hes1; cardiovascular developmental process. Reason: Pleiotropic vascular developmental role; non-core. Supporting Evidence: file:human/HES1/HES1-uniprot.txt P:vascular associated smooth muscle cell development |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:12535671 Human Sir2-related protein SIRT1 associates with the bHLH re... | ACCEPT | Summary: Reporter-assay evidence that HES1 represses transcription, with SIRT1-dependent and -independent deacetylase pathways contributing to repression. Reason: Core repressor function with direct experimental support; clarifies the deacetylase-dependent mechanism. Supporting Evidence: PMID:12535671 both SIRT1-dependent and -independent deacetylase pathways are involved in the transcriptional repressions mediated by these bHLH repressors |
| GO:0042826 histone deacetylase binding | IPI PMID:12535671 Human Sir2-related protein SIRT1 associates with the bHLH re... | ACCEPT | Summary: HES1 physically associates with SIRT1, an NAD+-dependent deacetylase, both in vitro and in vivo, recruiting deacetylase activity for repression. Reason: Directly demonstrated interaction with a deacetylase (SIRT1), a mechanistically informative molecular-function annotation (preferable to bare protein binding). Supporting Evidence: PMID:12535671 SIRT1, also physically associates with the human bHLH repressor proteins, hHES1 and hHEY2, both in vitro and in vivo |
| GO:0045892 negative regulation of DNA-templated transcription | IDA PMID:12535671 Human Sir2-related protein SIRT1 associates with the bHLH re... | ACCEPT | Summary: Direct evidence that HES1 represses DNA-templated transcription via deacetylase-dependent mechanisms (SIRT1). Reason: Core repressor function; directly supported. Supporting Evidence: PMID:12535671 involved in HES1- and HEY2-mediated transcriptional repression |
| GO:0007219 Notch signaling pathway | IDA PMID:16160079 Conservation of the Notch1 signaling pathway in gastrointest... | ACCEPT | Summary: In human carcinoid (BON) cells, inducible Notch1 activation directly increased HES1 protein, demonstrating HES1 as a Notch-pathway target/effector. Reason: Direct human evidence placing HES1 in the Notch signaling pathway. Supporting Evidence: PMID:16160079 Notch1 pathway activation led to an increase in hairy enhancer of split 1 (HES-1) protein |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-2220979 | ACCEPT | Summary: Reactome curation places HES1 in the nucleoplasm in the context of NOTCH1 PEST-domain mutants stimulating HES1 transcription. Reason: Consistent with the experimentally established nuclear/nucleoplasmic location. Supporting Evidence: file:human/HES1/HES1-uniprot.txt C:nucleoplasm; IDA:HPA |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-8878243 | ACCEPT | Summary: Reactome curation places HES1 in the nucleoplasm in the context of RUNX3-mediated inhibition of HES1 gene transcription. Reason: Consistent with the established nucleoplasmic location. Supporting Evidence: file:human/HES1/HES1-uniprot.txt C:nucleoplasm; IDA:HPA |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9013711 | ACCEPT | Summary: Reactome curation places HES1 in the nucleoplasm in the context of NOTCH4-stimulated HES1 gene expression. Reason: Consistent with the established nucleoplasmic location. Supporting Evidence: file:human/HES1/HES1-uniprot.txt C:nucleoplasm; IDA:HPA |
| GO:0003677 DNA binding | TAS PMID:7906273 Structure, chromosomal locus, and promoter analysis of the g... | ACCEPT | Summary: Traceable author statement that HES1 binds DNA (N-box elements), from the foundational characterization of the HES-1 promoter and autoregulation. Reason: Accurate DNA-binding annotation; the more specific N-box/E-box and sequence-specific terms are also present. Supporting Evidence: PMID:7906273 DNase I foot-printing and gel mobility shift analyses show that HES-1 binds to these sequences |
| GO:0007399 nervous system development | TAS PMID:8020957 Genomic cloning and chromosomal localization of HRY, the hum... | KEEP AS NON CORE | Summary: Traceable author statement linking the human hairy homolog (HRY/HES1) to nervous system development, consistent with its role in suppressing neuronal differentiation. Reason: Broad neural-development process; a pleiotropic developmental output of HES1 repressor activity, non-core relative to molecular function. Supporting Evidence: PMID:8020957 can, like that in Drosophila, suppress neuronal differentiation events |
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Download this section (compressed HTML)Q: Should HES1's ultradian oscillatory expression (negative autoregulation generating ~2-hour periodicity) be represented by a dedicated GO biological-process term, given its functional importance for progenitor fate decisions?
Suggested experts: Kageyama R
Q: Are the JAK-STAT cross-talk and JUN kinase binding annotations supported by direct human evidence, or are they ortholog projections that should be removed for the human protein?
Suggested experts: Kageyama R
Experiment: Compare DNA binding (ChIP-seq/EMSA) and repression activity (reporter assays, target gene expression) of wild-type HES1 versus WRPW-deleted and Orange-domain mutants in human neural progenitor cells.
Hypothesis: HES1 represses target genes through a WRPW-dependent Groucho/TLE corepressor module together with deacetylase recruitment, and disrupting the WRPW motif abolishes repression without abolishing DNA binding.
Type: structure-function mutagenesis and repression assay
Experiment: Perform endogenous HES1 ChIP-seq with motif analysis in synchronized human progenitor cells across the oscillation cycle, integrating with nascent-transcription (e.g., PRO-seq) readouts.
Hypothesis: HES1 occupancy genome-wide is enriched at N-box and E-box elements of proneural and cell-cycle genes, and its oscillation dynamically switches target occupancy.
Type: genome-wide occupancy and motif analysis
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