HES1

id: Q14469
gene_symbol: HES1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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).
existing_annotations:
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:7906273
          supporting_text: it binds more preferentially to the N box (CACNAG)
            than to the E box (CANNTG) and acts as a negative regulator
        - reference_id: PMID:12535671
          supporting_text: involved in HES1- and HEY2-mediated transcriptional
            repression
  - term:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase
        II-specific
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:7906273
          supporting_text: HES-1 binds to these sequences
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Nuclear localization inferred phylogenetically, consistent with HES1
        acting as a DNA-binding nuclear transcription factor.
      action: ACCEPT
      reason: >-
        HES1 is a transcription factor whose site of action is the nucleus;
        UniProt records Nucleus as the subcellular location.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
  - term:
      id: GO:0007219
      label: Notch signaling pathway
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      reason: >-
        Acting as a transcriptional effector of Notch is a defining feature of
        HES1. Directly demonstrated in human cells where Notch1 activation
        increases HES1.
      supported_by:
        - reference_id: PMID:16160079
          supporting_text: Notch1 pathway activation led to an increase in hairy
            enhancer of split 1 (HES-1) protein
  - term:
      id: GO:0009952
      label: anterior/posterior pattern specification
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: file:human/HES1/HES1-deep-research-falcon.md
          supporting_text: HES1/Hes-family oscillators coordinate segmentation
            clock and neurogenic timing
  - term:
      id: GO:0045665
      label: negative regulation of neuron differentiation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:19682396
          supporting_text: inactivation of Notch-regulated genes such as Hes1 and
            Hes5 induced a premature neuronal differentiation during brain
            development
  - term:
      id: GO:0050767
      label: regulation of neurogenesis
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        Regulation of neurogenesis is a broad neural-development process
        downstream of HES1 repressor activity; HES1 controls timing and
        progenitor maintenance during neurogenesis.
      action: KEEP_AS_NON_CORE
      reason: >-
        Valid pleiotropic developmental role, parent of the negative regulation
        of neuron differentiation that HES1 executes; non-core relative to
        molecular function.
      supported_by:
        - reference_id: PMID:19682396
          supporting_text: Notch signaling, which maintains stem cell
            characteristics of in-vivo-derived neuroprogenitors
  - term:
      id: GO:0070888
      label: E-box binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        HES1 binds E-box motifs (CANNTG), albeit with lower affinity than N-box.
        Phylogenetically supported and consistent with bHLH biology.
      action: ACCEPT
      reason: >-
        HES1 binds E-box elements (low affinity) in addition to its preferred
        N-box; a genuine DNA-binding specificity of the protein.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: Binds DNA on N-box motifs 5'-CACNAG-3' with high
            affinity and on E-box motifs 5'-CANNTG-3' with low affinity
  - term:
      id: GO:0071820
      label: N-box binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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.
      action: ACCEPT
      reason: >-
        Core molecular function. N-box binding distinguishes HES1 from canonical
        E-box bHLH activators and underlies its autorepression.
      supported_by:
        - reference_id: PMID:7906273
          supporting_text: it binds more preferentially to the N box (CACNAG)
            than to the E box (CANNTG)
  - term:
      id: GO:0003677
      label: DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      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.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:7906273
          supporting_text: HES-1 binds to these sequences
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        Nuclear localization predicted by electronic methods, consistent with
        experimentally determined nuclear location.
      action: ACCEPT
      reason: >-
        HES1 is a nuclear transcription factor; UniProt records Nucleus as the
        subcellular location.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
  - term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        Broad transcription-regulation term assigned via InterPro (Orange
        domain). Correct but very general; HES1 acts specifically as a
        repressor.
      action: ACCEPT
      reason: >-
        A correct high-level parent term consistent with HES1 function; more
        specific repressor terms are also present.
      supported_by:
        - reference_id: PMID:7906273
          supporting_text: acts as a negative regulator
  - term:
      id: GO:0046983
      label: protein dimerization activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: >-
        Dimerization activity inferred from the HLH domain. HES1 functions as
        homo- and heterodimers via its helix-loop-helix, so this is accurate.
      action: ACCEPT
      reason: >-
        The HLH domain mediates dimerization, a prerequisite for DNA binding;
        supported by the protein homodimerization annotations.
      supported_by:
        - reference_id: file:human/HES1/HES1-deep-research-falcon.md
          supporting_text: HES1 is a transcriptional repressor that binds DNA as
            homo- or heterodimers
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:12535671
    review:
      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).
      action: MARK_AS_OVER_ANNOTATED
      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.
      supported_by:
        - reference_id: PMID:12535671
          supporting_text: SIRT1, also physically associates with the human bHLH
            repressor proteins, hHES1 and hHEY2, both in vitro and in vivo
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Ortholog-projected negative regulation of Pol II transcription, matching
        the core repressor role and direct human evidence.
      action: ACCEPT
      reason: >-
        Core function; duplicate of the IBA/IDA-supported repressor annotation.
      supported_by:
        - reference_id: PMID:12535671
          supporting_text: involved in HES1- and HEY2-mediated transcriptional
            repression
  - term:
      id: GO:0000785
      label: chromatin
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Localization to chromatin inferred by orthology, consistent with HES1
        binding promoter/enhancer DNA and recruiting chromatin-modifying
        corepressors.
      action: ACCEPT
      reason: >-
        A DNA-binding transcription factor that occupies target promoters is
        appropriately localized to chromatin.
      supported_by:
        - reference_id: PMID:7906273
          supporting_text: DNase I foot-printing and gel mobility shift analyses
            show that HES-1 binds to these sequences
  - term:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase
        II-specific
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Ortholog-projected Pol II transcription factor activity; correct parent
        term, duplicate of the IBA annotation.
      action: ACCEPT
      reason: >-
        Accurate; the repressor-specific child term GO:0001227 is the precise
        function and is also annotated.
      supported_by:
        - reference_id: PMID:7906273
          supporting_text: HES-1 binds to these sequences
  - term:
      id: GO:0001217
      label: DNA-binding transcription repressor activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        HES1 is a sequence-specific DNA-binding transcriptional repressor;
        accurate molecular-function term (parent of the Pol II-specific
        GO:0001227).
      action: ACCEPT
      reason: >-
        Core molecular function captured precisely. HES1 represses target
        promoters after DNA binding.
      supported_by:
        - reference_id: PMID:7906273
          supporting_text: cotransfection of the HES-1 expression vector leads to
            approximately 40-fold repression in promoter activity
  - term:
      id: GO:0001222
      label: transcription corepressor binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        HES1 binds Groucho/TLE corepressors via its WRPW motif, so binding of a
        transcription corepressor is well supported.
      action: ACCEPT
      reason: >-
        The C-terminal WRPW motif recruits TLE/Groucho corepressors, a defining
        mechanistic feature of HES1 repression.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: Interacts (via WPRW motif) with TLE1, and more weakly
            with TLE2
  - term:
      id: GO:0001227
      label: DNA-binding transcription repressor activity, RNA polymerase
        II-specific
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        The precise molecular function of HES1: a Pol II-specific
        sequence-specific DNA-binding transcriptional repressor. Strongly
        supported by direct repression assays.
      action: ACCEPT
      reason: >-
        This is HES1's core molecular function, capturing both DNA-binding and
        repressor activity at the right level of specificity.
      supported_by:
        - reference_id: PMID:7906273
          supporting_text: cotransfection of the HES-1 expression vector leads to
            approximately 40-fold repression in promoter activity
  - term:
      id: GO:0003143
      label: embryonic heart tube morphogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Developmental role in cardiac morphogenesis projected from ortholog
        phenotypes; a tissue-specific downstream effect of HES1 repressor
        activity.
      action: KEEP_AS_NON_CORE
      reason: >-
        Plausible pleiotropic developmental role (HES1 functions in
        cardiovascular development) but peripheral to the core molecular
        function.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:embryonic heart tube morphogenesis'
  - term:
      id: GO:0003281
      label: ventricular septum development
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Cardiac septation role projected by orthology; pleiotropic developmental
        output downstream of HES1.
      action: KEEP_AS_NON_CORE
      reason: >-
        Tissue-specific developmental process, non-core relative to molecular
        function.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:ventricular septum development'
  - term:
      id: GO:0003682
      label: chromatin binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Chromatin binding consistent with a promoter-occupying transcription
        factor; accurate but generic relative to sequence-specific DNA binding.
      action: ACCEPT
      reason: >-
        HES1 occupies target chromatin; consistent with its DNA-binding
        activity.
      supported_by:
        - reference_id: PMID:7906273
          supporting_text: HES-1 binds to these sequences
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      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.
      action: MARK_AS_OVER_ANNOTATED
      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.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
  - term:
      id: GO:0008432
      label: JUN kinase binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        JNK binding projected from an ortholog; not supported by direct human
        evidence and not a recognized core activity of HES1.
      action: UNDECIDED
      reason: >-
        This electronic ortholog projection cannot be verified against
        accessible human literature; no primary evidence for a HES1-JNK
        interaction is available here.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'F:JUN kinase binding; IEA:Ensembl'
  - term:
      id: GO:0010628
      label: positive regulation of gene expression
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      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.
      action: MARK_AS_OVER_ANNOTATED
      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.
      supported_by:
        - reference_id: PMID:7906273
          supporting_text: acts as a negative regulator
  - term:
      id: GO:0010629
      label: negative regulation of gene expression
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Negative regulation of gene expression, consistent with HES1's repressor
        function (a parent of the Pol II repression term).
      action: ACCEPT
      reason: >-
        Accurate process term reflecting HES1 repression of target genes.
      supported_by:
        - reference_id: PMID:7906273
          supporting_text: acts as a negative regulator
  - term:
      id: GO:0010977
      label: negative regulation of neuron projection development
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Neuron projection (neurite) suppression projected from orthologs; a
        neural-differentiation-related downstream effect of HES1 repression.
      action: KEEP_AS_NON_CORE
      reason: >-
        Plausible neural developmental role consistent with HES1 inhibiting
        neuronal differentiation, but tissue-specific and non-core.
      supported_by:
        - reference_id: PMID:8020957
          supporting_text: can, like that in Drosophila, suppress neuronal
            differentiation events
  - term:
      id: GO:0016363
      label: nuclear matrix
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Nuclear matrix localization projected from orthologs; a subnuclear
        compartment consistent with nuclear function but not specifically
        characterized for human HES1.
      action: KEEP_AS_NON_CORE
      reason: >-
        Consistent with nuclear localization but a more specific subnuclear
        claim without direct human support; nucleus/nucleoplasm are the
        well-supported locations.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
  - term:
      id: GO:0021861
      label: forebrain radial glial cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        HES1 maintains radial glia/neural progenitors in the forebrain, delaying
        neuronal differentiation; tissue-specific developmental role.
      action: KEEP_AS_NON_CORE
      reason: >-
        Well-aligned with HES1 progenitor-maintenance function but a
        tissue-specific developmental process, hence non-core.
      supported_by:
        - reference_id: PMID:19682396
          supporting_text: maintain stem cell characteristics mainly through
            Notch signaling
  - term:
      id: GO:0030182
      label: neuron differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Generic neuron differentiation process projected from orthologs. HES1
        specifically acts to negatively regulate neuronal differentiation,
        captured better by GO:0045665.
      action: MODIFY
      reason: >-
        HES1 inhibits rather than promotes neuron differentiation; the bare
        neuron differentiation term loses directionality. Replace with the
        negative regulation term already supported.
      proposed_replacement_terms:
        - id: GO:0045665
          label: negative regulation of neuron differentiation
      supported_by:
        - reference_id: PMID:19682396
          supporting_text: inactivation of Notch-regulated genes such as Hes1 and
            Hes5 induced a premature neuronal differentiation
  - term:
      id: GO:0032991
      label: protein-containing complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      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.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Root-level protein-containing complex carries no specific information;
        the meaningful complex relationships are captured by
        corepressor/dimerization annotations.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: Transcription repression requires formation of a
            complex with a corepressor protein of the Groucho/TLE family
  - term:
      id: GO:0035315
      label: hair cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Inner-ear hair cell differentiation role projected from orthologs; HES1
        negatively regulates auditory hair-cell fate, a tissue-specific
        developmental output.
      action: KEEP_AS_NON_CORE
      reason: >-
        Valid pleiotropic developmental role in the inner ear, non-core relative
        to molecular function.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:hair cell differentiation'
  - term:
      id: GO:0035909
      label: aorta morphogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Aortic morphogenesis role projected from orthologs; cardiovascular
        developmental process downstream of HES1.
      action: KEEP_AS_NON_CORE
      reason: 'Pleiotropic cardiovascular developmental role; non-core.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:aorta morphogenesis'
  - term:
      id: GO:0035910
      label: ascending aorta morphogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Ascending-aorta morphogenesis projected from orthologs; tissue-specific
        cardiovascular developmental process.
      action: KEEP_AS_NON_CORE
      reason: 'Pleiotropic cardiovascular developmental role; non-core.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:ascending aorta morphogenesis'
  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Identical-protein binding reflects HES1 homodimerization. Accurate, but
        the more informative homodimerization activity term is also annotated.
      action: ACCEPT
      reason: >-
        HES1 forms homodimers via its HLH domain; identical protein binding is
        consistent with this.
      supported_by:
        - reference_id: file:human/HES1/HES1-deep-research-falcon.md
          supporting_text: HES1 is a transcriptional repressor that binds DNA as
            homo- or heterodimers
  - term:
      id: GO:0042803
      label: protein homodimerization activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        HES1 homodimerizes through its helix-loop-helix domain to bind DNA; well
        supported molecular function.
      action: ACCEPT
      reason: >-
        Homodimerization is a prerequisite for DNA binding by bHLH proteins and
        is documented for HES1.
      supported_by:
        - reference_id: file:human/HES1/HES1-deep-research-falcon.md
          supporting_text: HES1 is a transcriptional repressor that binds DNA as
            homo- or heterodimers
  - term:
      id: GO:0043254
      label: regulation of protein-containing complex assembly
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      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.
      action: UNDECIDED
      reason: >-
        This electronic projection lacks accessible primary support for human
        HES1; cannot be confirmed or refuted from available evidence.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:regulation of protein-containing complex assembly'
  - term:
      id: GO:0043279
      label: response to alkaloid
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Response to alkaloid projected from a rodent ortholog (likely a
        pharmacological treatment phenotype); not a core or human-validated
        function.
      action: UNDECIDED
      reason: >-
        Generic chemical-response term from ortholog projection without
        accessible human evidence; cannot be verified.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:response to alkaloid; IEA:Ensembl'
  - term:
      id: GO:0043398
      label: HLH domain binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Binding to other HLH-domain proteins is consistent with HES1
        heterodimerization with bHLH partners (e.g., HES6) and sequestration of
        proneural bHLH factors.
      action: ACCEPT
      reason: >-
        HES1 interacts with HLH-domain proteins through its own HLH domain
        (heterodimerization / sequestration of bHLH activators).
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: Interacts with HES6
  - term:
      id: GO:0043565
      label: sequence-specific DNA binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Sequence-specific DNA binding, consistent with HES1's recognition of
        N-box and E-box motifs.
      action: ACCEPT
      reason: >-
        HES1 binds defined DNA sequence motifs; accurate parent of the
        N-box/E-box terms.
      supported_by:
        - reference_id: PMID:7906273
          supporting_text: it binds more preferentially to the N box (CACNAG)
  - term:
      id: GO:0044877
      label: protein-containing complex binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      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.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Uninformative high-level binding term; specific interactions
        (corepressor binding, HDAC binding) capture the meaningful biology.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: Interacts with an FA complex, composed of FANCA,
            FANCF, FANCG and FANCL
  - term:
      id: GO:0045687
      label: positive regulation of glial cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      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.
      action: KEEP_AS_NON_CORE
      reason: >-
        Plausible developmental consequence of HES1 maintaining progenitors long
        enough to permit gliogenesis; non-core and tissue-specific.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:positive regulation of astrocyte differentiation'
  - term:
      id: GO:0045747
      label: positive regulation of Notch signaling pathway
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      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.
      action: UNDECIDED
      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.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:positive regulation of Notch signaling pathway'
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        Negative regulation of DNA-templated transcription, the general
        biological-process expression of HES1's repressor activity. Directly
        supported in human cells.
      action: ACCEPT
      reason: >-
        Core repressor function; consistent with direct repression assays and
        the SIRT1 study.
      supported_by:
        - reference_id: PMID:12535671
          supporting_text: involved in HES1- and HEY2-mediated transcriptional
            repression
  - term:
      id: GO:0045893
      label: positive regulation of DNA-templated transcription
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Positive regulation of DNA-templated transcription projected from
        orthologs. Conflicts with HES1's established role as a repressor; any
        activation is indirect.
      action: MARK_AS_OVER_ANNOTATED
      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.
      supported_by:
        - reference_id: PMID:7906273
          supporting_text: acts as a negative regulator
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Positive regulation of Pol II transcription projected from orthologs;
        contradicts the predominant repressor role of HES1.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        HES1 acts as a Pol II repressor; positive Pol II regulation is at most
        indirect (de-repression) and conflicts with its core function.
      supported_by:
        - reference_id: PMID:7906273
          supporting_text: acts as a negative regulator
  - term:
      id: GO:0045977
      label: positive regulation of mitotic cell cycle, embryonic
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        HES1 promotes proliferation/cell-cycle progression of embryonic
        progenitors (consistent with progenitor maintenance); projected from
        orthologs.
      action: KEEP_AS_NON_CORE
      reason: >-
        Consistent with HES1 keeping progenitors proliferative, but a
        tissue/stage-specific developmental output rather than the core
        molecular function.
      supported_by:
        - reference_id: PMID:19682396
          supporting_text: proliferation potential in the NESs
  - term:
      id: GO:0046425
      label: regulation of receptor signaling pathway via JAK-STAT
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      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.
      action: KEEP_AS_NON_CORE
      reason: >-
        Context-dependent signaling cross-talk (HES1-STAT3/JAK axis) is reported
        but peripheral to the core repressor function.
      supported_by:
        - reference_id: file:human/HES1/HES1-deep-research-falcon.md
          supporting_text: HES1 can bind STAT3 and facilitate its phosphorylation
            via JAK2
  - term:
      id: GO:0046427
      label: positive regulation of receptor signaling pathway via JAK-STAT
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Positive regulation of JAK-STAT signaling projected from orthologs;
        aligns with reported HES1 promotion of STAT3 phosphorylation.
      action: KEEP_AS_NON_CORE
      reason: >-
        Reported signaling cross-talk role, non-core relative to molecular
        function.
      supported_by:
        - reference_id: file:human/HES1/HES1-deep-research-falcon.md
          supporting_text: HES1 can bind STAT3 and facilitate its phosphorylation
            via JAK2
  - term:
      id: GO:0048538
      label: thymus development
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Thymus development role projected from orthologs; HES1 functions
        downstream of Notch in T-lineage/thymic development.
      action: KEEP_AS_NON_CORE
      reason: >-
        Pleiotropic immune/developmental role consistent with Notch-HES1
        function in the thymus; non-core.
      supported_by:
        - reference_id: PMID:12032823
          supporting_text: its interference with lymphoid B and myeloid
            maturation is partly mediated by Hes1 and Hes5
  - term:
      id: GO:0048711
      label: positive regulation of astrocyte differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Positive regulation of astrocyte (glial) differentiation, a
        developmental consequence of HES1 delaying neurogenesis; projected from
        orthologs.
      action: KEEP_AS_NON_CORE
      reason: >-
        Tissue-specific developmental role consistent with HES1 promoting
        gliogenesis at the expense of neurogenesis; non-core.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:positive regulation of astrocyte differentiation'
  - term:
      id: GO:0048715
      label: negative regulation of oligodendrocyte differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        Negative regulation of oligodendrocyte differentiation, consistent with
        HES1 repression of differentiation programs; projected electronically.
      action: KEEP_AS_NON_CORE
      reason: >-
        Tissue-specific glial developmental role downstream of HES1 repressor
        activity; non-core.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:negative regulation of oligodendrocyte
            differentiation'
  - term:
      id: GO:0048844
      label: artery morphogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Artery morphogenesis role projected from orthologs; cardiovascular
        developmental process downstream of HES1/Notch.
      action: KEEP_AS_NON_CORE
      reason: 'Pleiotropic vascular developmental role; non-core.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:artery morphogenesis'
  - term:
      id: GO:0050768
      label: negative regulation of neurogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Negative regulation of neurogenesis, a central neural role of HES1
        (suppressing proneural genes to maintain progenitors); projected
        electronically.
      action: KEEP_AS_NON_CORE
      reason: >-
        Well-supported neural developmental role consistent with HES1 function,
        but a process-level output, hence non-core.
      supported_by:
        - reference_id: PMID:8020957
          supporting_text: can, like that in Drosophila, suppress neuronal
            differentiation events
  - term:
      id: GO:0051087
      label: protein-folding chaperone binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Chaperone binding projected from an ortholog; not supported by
        accessible human evidence and not a recognized HES1 function.
      action: UNDECIDED
      reason: >-
        Electronic ortholog projection without verifiable human support; cannot
        confirm or refute.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'F:protein-folding chaperone binding; IEA:Ensembl'
  - term:
      id: GO:0060253
      label: negative regulation of glial cell proliferation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Negative regulation of glial cell proliferation projected from
        orthologs; a tissue-specific developmental role.
      action: KEEP_AS_NON_CORE
      reason: 'Plausible context-specific role downstream of HES1; non-core.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:negative regulation of glial cell proliferation'
  - term:
      id: GO:0060412
      label: ventricular septum morphogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Cardiac septum morphogenesis projected from orthologs; cardiovascular
        developmental output of HES1.
      action: KEEP_AS_NON_CORE
      reason: 'Pleiotropic cardiovascular developmental role; non-core.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:ventricular septum morphogenesis'
  - term:
      id: GO:0060675
      label: ureteric bud morphogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Ureteric bud morphogenesis projected from orthologs; HES1 has documented
        roles in kidney development.
      action: KEEP_AS_NON_CORE
      reason: 'Pleiotropic renal developmental role; non-core.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:ureteric bud morphogenesis'
  - term:
      id: GO:0060716
      label: labyrinthine layer blood vessel development
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Placental labyrinth vascular development projected from orthologs;
        tissue-specific developmental process.
      action: KEEP_AS_NON_CORE
      reason: 'Pleiotropic placental/vascular developmental role; non-core.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:labyrinthine layer blood vessel development'
  - term:
      id: GO:0061626
      label: pharyngeal arch artery morphogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Pharyngeal arch artery morphogenesis projected from orthologs;
        cardiovascular developmental process.
      action: KEEP_AS_NON_CORE
      reason: 'Pleiotropic cardiovascular developmental role; non-core.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:pharyngeal arch artery morphogenesis'
  - term:
      id: GO:0061629
      label: RNA polymerase II-specific DNA-binding transcription factor binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Binding to Pol II transcription factors, consistent with HES1
        sequestering/repressing proneural bHLH activators (e.g., interfering
        with E2A/E47 and MYOD1).
      action: ACCEPT
      reason: >-
        HES1 binds and antagonizes other Pol II transcription factors
        (E-proteins, MYOD1), a documented mechanism of its repressor action.
      supported_by:
        - reference_id: PMID:12032823
          supporting_text: their ability to interfere with the transcriptional
            activity of E2A in a reporter assay
  - term:
      id: GO:0065003
      label: protein-containing complex assembly
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Generic complex-assembly process projected from orthologs. HES1
        nucleates repressor complexes and supports FA core complex stability, but
        this broad term is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Very general process term; specific complex relationships (corepressor
        recruitment, FA core complex) are captured elsewhere.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: required for the stability and nuclear localization of
            FA core complex proteins
  - term:
      id: GO:0070888
      label: E-box binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        E-box binding (electronic), duplicate of the IBA/ISS annotations; HES1
        binds E-box with lower affinity than N-box.
      action: ACCEPT
      reason: 'Genuine low-affinity DNA-binding specificity of HES1.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: on E-box motifs 5'-CANNTG-3' with low affinity
  - term:
      id: GO:0071347
      label: cellular response to interleukin-1
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Response to IL-1 projected from a rodent ortholog; an inducible
        expression/response phenotype rather than a core function.
      action: UNDECIDED
      reason: >-
        Electronic ortholog projection of a stimulus-response phenotype without
        accessible human support; cannot verify.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:cellular response to interleukin-1'
  - term:
      id: GO:0071356
      label: cellular response to tumor necrosis factor
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Response to TNF projected from a rodent ortholog; inducible response
        phenotype rather than a core function.
      action: UNDECIDED
      reason: 'Electronic ortholog projection without verifiable human support.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:cellular response to tumor necrosis factor'
  - term:
      id: GO:0071398
      label: cellular response to fatty acid
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Response to fatty acid projected from a rodent ortholog; inducible
        response phenotype, not a core function.
      action: UNDECIDED
      reason: 'Electronic ortholog projection without verifiable human support.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:cellular response to fatty acid'
  - term:
      id: GO:0071820
      label: N-box binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        N-box binding (electronic), duplicate of the IBA/ISS annotations; the
        signature high-affinity DNA recognition of HES1.
      action: ACCEPT
      reason: 'Core DNA-binding specificity of HES1.'
      supported_by:
        - reference_id: PMID:7906273
          supporting_text: it binds more preferentially to the N box (CACNAG)
  - term:
      id: GO:0072012
      label: glomerulus vasculature development
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Glomerular vasculature development projected from orthologs;
        renal/vascular developmental process.
      action: KEEP_AS_NON_CORE
      reason: 'Pleiotropic renal developmental role; non-core.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:glomerulus vasculature development'
  - term:
      id: GO:0072049
      label: comma-shaped body morphogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Comma-shaped body morphogenesis (nephron development) projected from
        orthologs; renal developmental process.
      action: KEEP_AS_NON_CORE
      reason: 'Pleiotropic renal developmental role; non-core.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:comma-shaped body morphogenesis'
  - term:
      id: GO:0072050
      label: S-shaped body morphogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        S-shaped body morphogenesis (nephron development) projected from
        orthologs; renal developmental process.
      action: KEEP_AS_NON_CORE
      reason: 'Pleiotropic renal developmental role; non-core.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:S-shaped body morphogenesis'
  - term:
      id: GO:0072141
      label: renal interstitial fibroblast development
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Renal interstitial fibroblast development projected from orthologs;
        kidney developmental process.
      action: KEEP_AS_NON_CORE
      reason: 'Pleiotropic renal developmental role; non-core.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:renal interstitial fibroblast development'
  - term:
      id: GO:0072282
      label: metanephric nephron tubule morphogenesis
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Metanephric nephron tubule morphogenesis projected from orthologs;
        kidney developmental process.
      action: KEEP_AS_NON_CORE
      reason: 'Pleiotropic renal developmental role; non-core.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:metanephric nephron tubule morphogenesis'
  - term:
      id: GO:0090281
      label: negative regulation of calcium ion import
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Negative regulation of calcium import projected from a rodent ortholog;
        not a recognized core function and not supported by accessible human
        evidence.
      action: UNDECIDED
      reason: >-
        Electronic ortholog projection of a specialized phenotype without
        verifiable human support.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:negative regulation of calcium ion import'
  - term:
      id: GO:0097066
      label: response to thyroid hormone
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Response to thyroid hormone projected from a rodent ortholog; an
        inducible-response phenotype, not a core function.
      action: UNDECIDED
      reason: 'Electronic ortholog projection without verifiable human support.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:response to thyroid hormone'
  - term:
      id: GO:0097084
      label: vascular associated smooth muscle cell development
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Vascular smooth muscle cell development projected from orthologs;
        cardiovascular developmental process downstream of HES1/Notch.
      action: KEEP_AS_NON_CORE
      reason: 'Pleiotropic vascular developmental role; non-core.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:vascular associated smooth muscle cell development'
  - term:
      id: GO:0097150
      label: neuronal stem cell population maintenance
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        Maintenance of the neural stem-cell pool, a hallmark HES1 role
        (electronic duplicate of the IEP annotation from PMID:19682396).
      action: KEEP_AS_NON_CORE
      reason: >-
        Central neural-progenitor role of HES1, but a process-level
        developmental output; non-core relative to molecular function.
      supported_by:
        - reference_id: PMID:19682396
          supporting_text: maintain stem cell characteristics mainly through
            Notch signaling
  - term:
      id: GO:1904010
      label: response to Aroclor 1254
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Response to the PCB mixture Aroclor 1254, projected from a rodent
        ortholog; a toxicological treatment phenotype, not a core function.
      action: UNDECIDED
      reason: >-
        Highly specific chemical-response phenotype from ortholog projection
        without verifiable human support.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:response to Aroclor 1254'
  - term:
      id: GO:1990090
      label: cellular response to nerve growth factor stimulus
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      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.
      action: UNDECIDED
      reason: >-
        Ortholog projection of a growth-factor response phenotype without
        verifiable human support.
      supported_by:
        - reference_id: PMID:8020957
          supporting_text: behaves as an immediate-early gene in its response to
            growth factors
  - term:
      id: GO:2000978
      label: negative regulation of forebrain neuron differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Negative regulation of forebrain neuron differentiation, a specific
        neural role of HES1 in maintaining forebrain progenitors; electronic
        duplicate of the ISS annotation.
      action: KEEP_AS_NON_CORE
      reason: >-
        Tissue-specific neural developmental role consistent with HES1
        repression of neuronal differentiation; non-core.
      supported_by:
        - reference_id: PMID:19682396
          supporting_text: inactivation of Notch-regulated genes such as Hes1 and
            Hes5 induced a premature neuronal differentiation
  - term:
      id: GO:2000981
      label: negative regulation of inner ear receptor cell differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        Negative regulation of inner ear receptor cell (hair cell)
        differentiation projected from orthologs; tissue-specific developmental
        role.
      action: KEEP_AS_NON_CORE
      reason: >-
        Pleiotropic inner-ear developmental role downstream of HES1 repressor
        activity; non-core.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:negative regulation of inner ear auditory receptor
            cell differentiation'
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: >-
        Direct immunofluorescence (Human Protein Atlas) localizes HES1 to the
        nucleoplasm, consistent with its role as a nuclear transcription factor.
      action: ACCEPT
      reason: >-
        Experimental localization supporting the nuclear/nucleoplasmic site of
        action.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'C:nucleoplasm; IDA:HPA'
  - term:
      id: GO:0001227
      label: DNA-binding transcription repressor activity, RNA polymerase
        II-specific
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Sequence-similarity-based assignment of the precise repressor activity,
        transferred from mouse Hes1 (P35428). Matches direct human repression
        data.
      action: ACCEPT
      reason: >-
        Core molecular function; well supported and consistent with the IEA and
        experimental evidence.
      supported_by:
        - reference_id: PMID:7906273
          supporting_text: cotransfection of the HES-1 expression vector leads to
            approximately 40-fold repression in promoter activity
  - term:
      id: GO:1990837
      label: sequence-specific double-stranded DNA binding
    evidence_type: IDA
    original_reference_id: PMID:28473536
    review:
      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.
      action: ACCEPT
      reason: >-
        Direct experimental demonstration of sequence-specific dsDNA binding by
        human HES1 (SELEX), supporting its DNA-binding function.
      supported_by:
        - reference_id: PMID:28473536
          supporting_text: systematic analysis of DNA binding specificities of
            full-length TFs and eDBDs using unmethylated and CpG-methylated DNA
            ligands
  - term:
      id: GO:0061629
      label: RNA polymerase II-specific DNA-binding transcription factor binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Binding to Pol II transcription factors transferred by similarity from
        mouse Hes1; consistent with HES1 antagonizing E-proteins/proneural bHLH
        activators.
      action: ACCEPT
      reason: >-
        HES1 binds and inhibits other Pol II transcription factors (E2A/E47,
        MYOD1); supported by reporter-assay interference data.
      supported_by:
        - reference_id: PMID:12032823
          supporting_text: their ability to interfere with the transcriptional
            activity of E2A in a reporter assay
  - term:
      id: GO:0070888
      label: E-box binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        E-box binding transferred by similarity from mouse Hes1; low-affinity
        DNA-binding specificity of HES1.
      action: ACCEPT
      reason: >-
        Genuine DNA-binding specificity; duplicate of IBA/IEA E-box annotations.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: on E-box motifs 5'-CANNTG-3' with low affinity
  - term:
      id: GO:0071820
      label: N-box binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        N-box binding transferred by similarity from mouse Hes1; the signature
        high-affinity DNA recognition of HES1.
      action: ACCEPT
      reason: >-
        Core DNA-binding specificity; duplicate of IBA/IEA N-box annotations.
      supported_by:
        - reference_id: PMID:7906273
          supporting_text: it binds more preferentially to the N box (CACNAG)
  - term:
      id: GO:0061626
      label: pharyngeal arch artery morphogenesis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Pharyngeal arch artery morphogenesis transferred by similarity from
        mouse Hes1; cardiovascular developmental process.
      action: KEEP_AS_NON_CORE
      reason: 'Pleiotropic cardiovascular developmental role; non-core.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:pharyngeal arch artery morphogenesis'
  - term:
      id: GO:0003143
      label: embryonic heart tube morphogenesis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Embryonic heart tube morphogenesis transferred by similarity from mouse
        Hes1; cardiovascular developmental process.
      action: KEEP_AS_NON_CORE
      reason: 'Pleiotropic cardiovascular developmental role; non-core.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:embryonic heart tube morphogenesis'
  - term:
      id: GO:0035910
      label: ascending aorta morphogenesis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Ascending aorta morphogenesis transferred by similarity from mouse Hes1;
        cardiovascular developmental process.
      action: KEEP_AS_NON_CORE
      reason: 'Pleiotropic cardiovascular developmental role; non-core.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:ascending aorta morphogenesis'
  - term:
      id: GO:0045977
      label: positive regulation of mitotic cell cycle, embryonic
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Positive regulation of embryonic mitotic cell cycle transferred by
        similarity; consistent with HES1 keeping progenitors proliferative.
      action: KEEP_AS_NON_CORE
      reason: >-
        Tissue/stage-specific proliferative role; non-core relative to molecular
        function.
      supported_by:
        - reference_id: PMID:19682396
          supporting_text: proliferation potential in the NESs
  - term:
      id: GO:0060412
      label: ventricular septum morphogenesis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Ventricular septum morphogenesis transferred by similarity from mouse
        Hes1; cardiovascular developmental process.
      action: KEEP_AS_NON_CORE
      reason: 'Pleiotropic cardiovascular developmental role; non-core.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:ventricular septum morphogenesis'
  - term:
      id: GO:2000978
      label: negative regulation of forebrain neuron differentiation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Negative regulation of forebrain neuron differentiation transferred by
        similarity; a specific neural role of HES1.
      action: KEEP_AS_NON_CORE
      reason: 'Tissue-specific neural developmental role; non-core.'
      supported_by:
        - reference_id: PMID:19682396
          supporting_text: inactivation of Notch-regulated genes such as Hes1 and
            Hes5 induced a premature neuronal differentiation
  - term:
      id: GO:0097150
      label: neuronal stem cell population maintenance
    evidence_type: IEP
    original_reference_id: PMID:19682396
    review:
      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.
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:19682396
          supporting_text: Notch signaling, which maintains stem cell
            characteristics of in-vivo-derived neuroprogenitors, is active in
            these hESC-derived NESs
  - term:
      id: GO:0007219
      label: Notch signaling pathway
    evidence_type: IMP
    original_reference_id: PMID:19682396
    review:
      summary: >-
        Mutant/perturbation phenotype (gamma-secretase inhibition of Notch) in
        human neuroprogenitors implicates HES1 as a Notch-pathway effector
        controlling stem-cell features.
      action: ACCEPT
      reason: >-
        HES1 acting in the Notch signaling pathway is a defining feature,
        supported here by perturbation of Notch in human cells.
      supported_by:
        - reference_id: PMID:19682396
          supporting_text: Inhibition of the Notch signaling by a gamma-secretase
            inhibitor reduced rosette structures, expression levels of NSC marker
            genes and proliferation potential
  - term:
      id: GO:0021861
      label: forebrain radial glial cell differentiation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Forebrain radial glial cell differentiation transferred by similarity;
        HES1 maintains radial glia/neural progenitors.
      action: KEEP_AS_NON_CORE
      reason: 'Tissue-specific neural developmental role; non-core.'
      supported_by:
        - reference_id: PMID:19682396
          supporting_text: maintain stem cell characteristics mainly through
            Notch signaling
  - term:
      id: GO:0042531
      label: positive regulation of tyrosine phosphorylation of STAT protein
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Positive regulation of STAT tyrosine phosphorylation transferred by
        similarity; aligns with reported HES1 promotion of STAT3 phosphorylation
        via JAK2.
      action: KEEP_AS_NON_CORE
      reason: >-
        Context-dependent signaling cross-talk role, peripheral to the core
        repressor function.
      supported_by:
        - reference_id: file:human/HES1/HES1-deep-research-falcon.md
          supporting_text: HES1 can bind STAT3 and facilitate its phosphorylation
            via JAK2
  - term:
      id: GO:0043388
      label: positive regulation of DNA binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Positive regulation of DNA binding transferred by similarity from mouse
        Hes1; mechanism for the human protein is not clearly defined.
      action: UNDECIDED
      reason: >-
        The biological meaning of this ISS-transferred term for human HES1 is
        unclear and not supported by accessible primary evidence.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:positive regulation of DNA binding'
  - term:
      id: GO:0043565
      label: sequence-specific DNA binding
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Sequence-specific DNA binding transferred by similarity; consistent with
        HES1 recognition of N-box/E-box motifs.
      action: ACCEPT
      reason: 'Accurate DNA-binding term; duplicate of the IEA and IDA support.'
      supported_by:
        - reference_id: PMID:7906273
          supporting_text: it binds more preferentially to the N box (CACNAG)
  - term:
      id: GO:0046425
      label: regulation of receptor signaling pathway via JAK-STAT
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Regulation of JAK-STAT signaling transferred by similarity; HES1
        cross-talk with STAT3/JAK is reported.
      action: KEEP_AS_NON_CORE
      reason: 'Context-dependent signaling cross-talk, non-core.'
      supported_by:
        - reference_id: file:human/HES1/HES1-deep-research-falcon.md
          supporting_text: HES1 can bind STAT3 and facilitate its phosphorylation
            via JAK2
  - term:
      id: GO:0046427
      label: positive regulation of receptor signaling pathway via JAK-STAT
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Positive regulation of JAK-STAT signaling transferred by similarity;
        aligns with reported HES1 promotion of STAT3 phosphorylation.
      action: KEEP_AS_NON_CORE
      reason: 'Context-dependent signaling cross-talk, non-core.'
      supported_by:
        - reference_id: file:human/HES1/HES1-deep-research-falcon.md
          supporting_text: HES1 can bind STAT3 and facilitate its phosphorylation
            via JAK2
  - term:
      id: GO:0065003
      label: protein-containing complex assembly
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Generic complex-assembly process transferred by similarity; HES1
        contributes to repressor and FA core complex assembly/stability but the
        broad term is uninformative.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        Very general process term; meaningful complex relationships are captured
        by specific corepressor/FA-complex annotations.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: required for the stability and nuclear localization of
            FA core complex proteins
  - term:
      id: GO:2000737
      label: negative regulation of stem cell differentiation
    evidence_type: IMP
    original_reference_id: PMID:19682396
    review:
      summary: >-
        Perturbation evidence that HES1 (downstream of Notch) suppresses
        differentiation of human neural stem cells, maintaining the progenitor
        state.
      action: KEEP_AS_NON_CORE
      reason: >-
        Well-supported stem-cell maintenance role, but a process-level
        developmental output; non-core relative to molecular function.
      supported_by:
        - reference_id: PMID:19682396
          supporting_text: if combined with withdrawal of growth factors,
            triggered differentiation toward neurons
  - term:
      id: GO:2000974
      label: negative regulation of pro-B cell differentiation
    evidence_type: IMP
    original_reference_id: PMID:12032823
    review:
      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.
      action: KEEP_AS_NON_CORE
      reason: >-
        Genuine experimentally supported hematopoietic role downstream of HES1
        repressor activity, but tissue-specific and non-core.
      supported_by:
        - reference_id: PMID:12032823
          supporting_text: cells transduced with Hes1 or Hes5 were partially
            impaired in their ability to differentiate into B cells
  - term:
      id: GO:0042803
      label: protein homodimerization activity
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Homodimerization activity transferred by similarity from mouse Hes1;
        HES1 binds DNA as a homodimer via its HLH domain.
      action: ACCEPT
      reason: >-
        Homodimerization is required for bHLH DNA binding; duplicate of the IEA
        annotation.
      supported_by:
        - reference_id: file:human/HES1/HES1-deep-research-falcon.md
          supporting_text: HES1 is a transcriptional repressor that binds DNA as
            homo- or heterodimers
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:12032823
    review:
      summary: >-
        Direct assay evidence that HES1 represses transcription, shown by
        interference with E2A transcriptional activity in a reporter assay.
      action: ACCEPT
      reason: 'Core repressor function with direct experimental support.'
      supported_by:
        - reference_id: PMID:12032823
          supporting_text: their ability to interfere with the transcriptional
            activity of E2A in a reporter assay was comparable to that of
            Notch1IC
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Nuclear localization transferred by similarity from mouse Hes1;
        consistent with experimentally determined nuclear location.
      action: ACCEPT
      reason: >-
        HES1 acts in the nucleus; duplicate of IBA/IEA nucleus annotations.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
  - term:
      id: GO:0048711
      label: positive regulation of astrocyte differentiation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Positive regulation of astrocyte differentiation transferred by
        similarity; developmental consequence of HES1 delaying neurogenesis.
      action: KEEP_AS_NON_CORE
      reason: 'Tissue-specific developmental role; non-core.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:positive regulation of astrocyte differentiation'
  - term:
      id: GO:0048715
      label: negative regulation of oligodendrocyte differentiation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Negative regulation of oligodendrocyte differentiation transferred by
        similarity; consistent with HES1 repression of differentiation.
      action: KEEP_AS_NON_CORE
      reason: 'Tissue-specific glial developmental role; non-core.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:negative regulation of oligodendrocyte
            differentiation'
  - term:
      id: GO:0060253
      label: negative regulation of glial cell proliferation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Negative regulation of glial cell proliferation transferred by
        similarity; tissue-specific developmental role.
      action: KEEP_AS_NON_CORE
      reason: 'Context-specific role downstream of HES1; non-core.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:negative regulation of glial cell proliferation'
  - term:
      id: GO:0003151
      label: outflow tract morphogenesis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Cardiac outflow tract morphogenesis transferred by similarity from mouse
        Hes1; cardiovascular developmental process.
      action: KEEP_AS_NON_CORE
      reason: 'Pleiotropic cardiovascular developmental role; non-core.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:outflow tract morphogenesis'
  - term:
      id: GO:0003281
      label: ventricular septum development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Ventricular septum development transferred by similarity from mouse
        Hes1; cardiovascular developmental process.
      action: KEEP_AS_NON_CORE
      reason: 'Pleiotropic cardiovascular developmental role; non-core.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:ventricular septum development'
  - term:
      id: GO:0008284
      label: positive regulation of cell population proliferation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Positive regulation of cell proliferation transferred by similarity;
        consistent with HES1 maintaining proliferative progenitors, though
        direction is context-dependent.
      action: KEEP_AS_NON_CORE
      reason: >-
        HES1 promotes progenitor proliferation in many contexts (and restrains
        it in others); a context-dependent developmental output, non-core.
      supported_by:
        - reference_id: PMID:19682396
          supporting_text: proliferation potential in the NESs
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Positive regulation of Pol II transcription transferred by similarity;
        contradicts the predominant repressor role of HES1.
      action: MARK_AS_OVER_ANNOTATED
      reason: >-
        HES1 is a Pol II repressor; positive Pol II regulation is at most
        indirect and conflicts with the core function.
      supported_by:
        - reference_id: PMID:7906273
          supporting_text: acts as a negative regulator
  - term:
      id: GO:0048538
      label: thymus development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Thymus development transferred by similarity from mouse Hes1;
        immune/developmental role downstream of Notch-HES1.
      action: KEEP_AS_NON_CORE
      reason: 'Pleiotropic immune/developmental role; non-core.'
      supported_by:
        - reference_id: PMID:12032823
          supporting_text: its interference with lymphoid B and myeloid
            maturation is partly mediated by Hes1 and Hes5
  - term:
      id: GO:0048844
      label: artery morphogenesis
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Artery morphogenesis transferred by similarity from mouse Hes1;
        cardiovascular developmental process.
      action: KEEP_AS_NON_CORE
      reason: 'Pleiotropic cardiovascular developmental role; non-core.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:artery morphogenesis'
  - term:
      id: GO:0097084
      label: vascular associated smooth muscle cell development
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: >-
        Vascular smooth muscle cell development transferred by similarity from
        mouse Hes1; cardiovascular developmental process.
      action: KEEP_AS_NON_CORE
      reason: 'Pleiotropic vascular developmental role; non-core.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'P:vascular associated smooth muscle cell development'
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IDA
    original_reference_id: PMID:12535671
    review:
      summary: >-
        Reporter-assay evidence that HES1 represses transcription, with
        SIRT1-dependent and -independent deacetylase pathways contributing to
        repression.
      action: ACCEPT
      reason: >-
        Core repressor function with direct experimental support; clarifies the
        deacetylase-dependent mechanism.
      supported_by:
        - reference_id: PMID:12535671
          supporting_text: both SIRT1-dependent and -independent deacetylase
            pathways are involved in the transcriptional repressions mediated by
            these bHLH repressors
  - term:
      id: GO:0042826
      label: histone deacetylase binding
    evidence_type: IPI
    original_reference_id: PMID:12535671
    review:
      summary: >-
        HES1 physically associates with SIRT1, an NAD+-dependent deacetylase,
        both in vitro and in vivo, recruiting deacetylase activity for
        repression.
      action: ACCEPT
      reason: >-
        Directly demonstrated interaction with a deacetylase (SIRT1), a
        mechanistically informative molecular-function annotation (preferable to
        bare protein binding).
      supported_by:
        - reference_id: PMID:12535671
          supporting_text: SIRT1, also physically associates with the human bHLH
            repressor proteins, hHES1 and hHEY2, both in vitro and in vivo
  - term:
      id: GO:0045892
      label: negative regulation of DNA-templated transcription
    evidence_type: IDA
    original_reference_id: PMID:12535671
    review:
      summary: >-
        Direct evidence that HES1 represses DNA-templated transcription via
        deacetylase-dependent mechanisms (SIRT1).
      action: ACCEPT
      reason: 'Core repressor function; directly supported.'
      supported_by:
        - reference_id: PMID:12535671
          supporting_text: involved in HES1- and HEY2-mediated transcriptional
            repression
  - term:
      id: GO:0007219
      label: Notch signaling pathway
    evidence_type: IDA
    original_reference_id: PMID:16160079
    review:
      summary: >-
        In human carcinoid (BON) cells, inducible Notch1 activation directly
        increased HES1 protein, demonstrating HES1 as a Notch-pathway
        target/effector.
      action: ACCEPT
      reason: 'Direct human evidence placing HES1 in the Notch signaling pathway.'
      supported_by:
        - reference_id: PMID:16160079
          supporting_text: Notch1 pathway activation led to an increase in hairy
            enhancer of split 1 (HES-1) protein
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-2220979
    review:
      summary: >-
        Reactome curation places HES1 in the nucleoplasm in the context of
        NOTCH1 PEST-domain mutants stimulating HES1 transcription.
      action: ACCEPT
      reason: >-
        Consistent with the experimentally established nuclear/nucleoplasmic
        location.
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'C:nucleoplasm; IDA:HPA'
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8878243
    review:
      summary: >-
        Reactome curation places HES1 in the nucleoplasm in the context of
        RUNX3-mediated inhibition of HES1 gene transcription.
      action: ACCEPT
      reason: 'Consistent with the established nucleoplasmic location.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'C:nucleoplasm; IDA:HPA'
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-9013711
    review:
      summary: >-
        Reactome curation places HES1 in the nucleoplasm in the context of
        NOTCH4-stimulated HES1 gene expression.
      action: ACCEPT
      reason: 'Consistent with the established nucleoplasmic location.'
      supported_by:
        - reference_id: file:human/HES1/HES1-uniprot.txt
          supporting_text: 'C:nucleoplasm; IDA:HPA'
  - term:
      id: GO:0003677
      label: DNA binding
    evidence_type: TAS
    original_reference_id: PMID:7906273
    review:
      summary: >-
        Traceable author statement that HES1 binds DNA (N-box elements), from
        the foundational characterization of the HES-1 promoter and
        autoregulation.
      action: ACCEPT
      reason: >-
        Accurate DNA-binding annotation; the more specific N-box/E-box and
        sequence-specific terms are also present.
      supported_by:
        - reference_id: PMID:7906273
          supporting_text: DNase I foot-printing and gel mobility shift analyses
            show that HES-1 binds to these sequences
  - term:
      id: GO:0007399
      label: nervous system development
    evidence_type: TAS
    original_reference_id: PMID:8020957
    review:
      summary: >-
        Traceable author statement linking the human hairy homolog (HRY/HES1) to
        nervous system development, consistent with its role in suppressing
        neuronal differentiation.
      action: KEEP_AS_NON_CORE
      reason: >-
        Broad neural-development process; a pleiotropic developmental output of
        HES1 repressor activity, non-core relative to molecular function.
      supported_by:
        - reference_id: PMID:8020957
          supporting_text: can, like that in Drosophila, suppress neuronal
            differentiation events
core_functions:
  - description: >-
      HES1 is a sequence-specific DNA-binding transcriptional repressor that
      binds N-box (CACNAG, high affinity) and E-box (CANNTG, low affinity)
      elements as a homo/heterodimer and represses RNA polymerase II
      transcription of target genes, including negative autoregulation of its
      own promoter.
    molecular_function:
      id: GO:0001227
      label: DNA-binding transcription repressor activity, RNA polymerase
        II-specific
    directly_involved_in:
      - id: GO:0000122
        label: negative regulation of transcription by RNA polymerase II
    locations:
      - id: GO:0005654
        label: nucleoplasm
    supported_by:
      - reference_id: PMID:7906273
        supporting_text: it binds more preferentially to the N box (CACNAG) than
          to the E box (CANNTG) and acts as a negative regulator
      - reference_id: PMID:7906273
        supporting_text: cotransfection of the HES-1 expression vector leads to
          approximately 40-fold repression in promoter activity
  - description: >-
      HES1 recruits transcriptional corepressors to silence target genes,
      binding Groucho/TLE corepressors through its C-terminal WRPW motif and
      associating with deacetylase activity (SIRT1) for repression.
    molecular_function:
      id: GO:0001222
      label: transcription corepressor binding
    directly_involved_in:
      - id: GO:0045892
        label: negative regulation of DNA-templated transcription
    locations:
      - id: GO:0005654
        label: nucleoplasm
    supported_by:
      - reference_id: file:human/HES1/HES1-uniprot.txt
        supporting_text: The C-terminal WRPW motif is a transcriptional
          repression domain necessary for the interaction with Groucho/TLE
          family members
      - reference_id: PMID:12535671
        supporting_text: both SIRT1-dependent and -independent deacetylase
          pathways are involved in the transcriptional repressions mediated by
          these bHLH repressors
  - description: >-
      HES1 is a downstream transcriptional effector of the Notch signaling
      pathway, activated by the Notch intracellular domain / RBPJ(CSL) complex,
      and it transduces Notch input into repression of proneural differentiation
      genes to maintain progenitor cells.
    molecular_function:
      id: GO:0061629
      label: RNA polymerase II-specific DNA-binding transcription factor
        binding
    directly_involved_in:
      - id: GO:0007219
        label: Notch signaling pathway
    locations:
      - id: GO:0005654
        label: nucleoplasm
    supported_by:
      - reference_id: PMID:16160079
        supporting_text: Notch1 pathway activation led to an increase in hairy
          enhancer of split 1 (HES-1) protein
      - reference_id: PMID:12032823
        supporting_text: their ability to interfere with the transcriptional
          activity of E2A in a reporter assay
proposed_new_terms: []
suggested_questions:
  - question: >-
      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?
    experts:
      - Kageyama R
  - question: >-
      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?
    experts:
      - Kageyama R
suggested_experiments:
  - 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.
    description: >-
      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.
    experiment_type: structure-function mutagenesis and repression assay
  - 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.
    description: >-
      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.
    experiment_type: genome-wide occupancy and motif analysis
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data
      to orthologs by curator judgment of sequence similarity
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation
      data to orthologs using Ensembl Compara
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:12032823
    title: Overexpression of the Notch target genes Hes in vivo induces lymphoid
      and myeloid alterations.
    findings:
      - statement: >-
          HES1 represses E2A (E-protein) transcriptional activity in reporter
          assays and impairs B-cell differentiation, demonstrating its repressor
          function and antagonism of proneural/E-protein bHLH activators.
        supporting_text: their ability to interfere with the transcriptional
          activity of E2A in a reporter assay was comparable to that of Notch1IC
  - id: PMID:12535671
    title: Human Sir2-related protein SIRT1 associates with the bHLH repressors
      HES1 and HEY2 and is involved in HES1- and HEY2-mediated transcriptional
      repression.
    findings:
      - statement: >-
          Human HES1 physically associates with the deacetylase SIRT1, and both
          SIRT1-dependent and -independent deacetylase pathways contribute to
          HES1-mediated transcriptional repression.
        supporting_text: SIRT1, also physically associates with the human bHLH
          repressor proteins, hHES1 and hHEY2, both in vitro and in vivo
  - id: PMID:16160079
    title: Conservation of the Notch1 signaling pathway in gastrointestinal
      carcinoid cells.
    findings:
      - statement: >-
          Inducible Notch1 activation in human carcinoid cells increases HES1
          protein, confirming HES1 as a downstream effector of Notch signaling.
        supporting_text: Notch1 pathway activation led to an increase in hairy
          enhancer of split 1 (HES-1) protein
  - id: PMID:19682396
    title: Notch signaling is required for maintaining stem-cell features of
      neuroprogenitor cells derived from human embryonic stem cells.
    findings:
      - statement: >-
          HES1 is expressed downstream of Notch in human hESC-derived
          neuroprogenitors; Notch inhibition reduces NSC markers and
          proliferation and triggers neuronal differentiation, implicating HES1
          in neural stem-cell maintenance.
        supporting_text: Inhibition of the Notch signaling by a gamma-secretase
          inhibitor reduced rosette structures, expression levels of NSC marker
          genes and proliferation potential
  - id: PMID:28473536
    title: Impact of cytosine methylation on DNA binding specificities of human
      transcription factors.
    findings:
      - statement: >-
          Human HES1 DNA-binding specificity was determined directly by
          methylation-sensitive SELEX in a genome-scale transcription-factor
          study, supporting sequence-specific double-stranded DNA binding.
        supporting_text: systematic analysis of DNA binding specificities of
          full-length TFs and eDBDs using unmethylated and CpG-methylated DNA
          ligands
  - id: PMID:7906273
    title: Structure, chromosomal locus, and promoter analysis of the gene
      encoding the mouse helix-loop-helix factor HES-1. Negative autoregulation
      through the multiple N box elements.
    findings:
      - statement: >-
          HES-1 binds N-box (CACNAG) elements preferentially over E-box, acts as
          a negative regulator, and negatively autoregulates its own promoter
          through N-box sequences.
        supporting_text: it binds more preferentially to the N box (CACNAG) than
          to the E box (CANNTG) and acts as a negative regulator
      - statement: >-
          HES-1 represses promoter activity ~40-fold, and disrupting the N-box
          sequences severely impairs this autoregulation.
        supporting_text: cotransfection of the HES-1 expression vector leads to
          approximately 40-fold repression in promoter activity
  - id: PMID:8020957
    title: Genomic cloning and chromosomal localization of HRY, the human
      homolog to the Drosophila segmentation gene, hairy.
    findings:
      - statement: >-
          The human hairy homolog (HRY/HES1) is structurally homologous to
          Drosophila hairy and the rat RHL immediate-early gene that suppresses
          neuronal differentiation, linking HES1 to nervous system development.
        supporting_text: can, like that in Drosophila, suppress neuronal
          differentiation events
  - id: Reactome:R-HSA-2220979
    title: NOTCH1 PEST domain mutants stimulate HES1 transcription
    findings: []
  - id: Reactome:R-HSA-8878243
    title: HES1 gene transcription is inhibited by RUNX3
    findings: []
  - id: Reactome:R-HSA-9013711
    title: HES1 gene expression is stimulated by NOTCH4
    findings: []
  - id: file:human/HES1/HES1-deep-research-falcon.md
    title: Deep research report on HES1
    findings:
      - statement: >-
          HES1 is a nuclear bHLH/Orange/WRPW transcriptional repressor and
          canonical Notch effector that binds N-box/class C motifs, recruits
          Groucho/TLE via WRPW, and oscillates to control developmental fate
          decisions.
        supporting_text: Human HES1 (Q14469) is a nuclear bHLH/Orange/WRPW
          transcriptional repressor and canonical NOTCH effector that binds
          N-box/class C motifs and recruits Groucho/TLE through WRPW to silence
          targets.