id: P14003 gene_symbol: hairy product_type: PROTEIN status: DRAFT taxon: id: NCBITaxon:7227 label: Drosophila melanogaster description: 'hairy (h) is a basic helix-loop-helix-Orange (bHLH-O), HES-family sequence-specific DNA-binding transcriptional repressor of Drosophila melanogaster. Through a repressor-type bHLH domain bearing a helix-interrupting proline it binds N-box (CACNAG) and related class-C/E-box sites in target promoters, and it represses transcription by recruiting the Groucho (Gro/TLE) corepressor through its C-terminal WRPW tetrapeptide, with an accessory, weaker interaction with the CtBP corepressor. Hairy is a primary pair-rule segmentation gene that patterns the anterior-posterior axis of the early embryo, repressing targets such as fushi tarazu, and it also patterns the adult peripheral nervous system, setting sensory bristle (chaeta) spacing by directly repressing the proneural achaete-scute genes. It acts in the nucleus and functions as a long-range transcriptional repressor. Its repressive activity is modulated post-translationally by RING/SUMO-targeted ubiquitin ligases (Topors, Degringolade) that bind Hairy and antagonize Groucho recruitment or trigger its degradation. Additional context-dependent roles include repression of metabolic genes contributing to hypoxia tolerance and, indirectly through its target genes, effects on epithelial tube (e.g. salivary gland) morphogenesis.' existing_annotations: - term: id: GO:0000122 label: negative regulation of transcription by RNA polymerase II evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: 'Phylogenetic (IBA) annotation of Hairy as a negative regulator of Pol II transcription. This is the central, well-supported function of Hairy as a bHLH-O repressor.' action: ACCEPT reason: 'Directly supported by experimental data showing Hairy is a transcriptional repressor of achaete and ftz, acting via Groucho recruitment. The IBA sits at an appropriate level of specificity for a HES-family repressor.' supported_by: - reference_id: PMID:7958929 supporting_text: transcriptional repressor - term: id: GO:0000981 label: DNA-binding transcription factor activity, RNA polymerase II-specific evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: 'Phylogenetic assignment of sequence-specific Pol II transcription factor activity. Correct at the family level; Hairy is more precisely a repressor (GO:0001227, separately annotated by IDA).' action: ACCEPT reason: 'Hairy is a sequence-specific Pol II DNA-binding transcription factor. The parent term is accurate; the repressor-specific child GO:0001227 captured elsewhere in this set gives the finer specificity, so this general IBA is retained rather than modified.' supported_by: - reference_id: PMID:7958929 supporting_text: DNA-binding protein and transcriptional repressor - term: id: GO:0005634 label: nucleus evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Phylogenetic localization to the nucleus, consistent with Hairy being a nuclear DNA-binding transcriptional repressor. action: ACCEPT reason: Hairy is a sequence-specific DNA-binding transcription factor and acts in the nucleus; UniProt records nuclear localization and the term is corroborated by IEA and IC annotations in this set. - term: id: GO:0009952 label: anterior/posterior pattern specification evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Phylogenetic annotation reflecting Hairy's role as a pair-rule gene patterning the anterior-posterior body axis of the embryo. action: ACCEPT reason: 'Hairy is a primary pair-rule segmentation gene; A/P pattern specification is an accurate parent process for its segmentation role.' supported_by: - reference_id: PMID:9524128 supporting_text: hairy is a Drosophila pair-rule segmentation gene that functions genetically as - term: id: GO:0050767 label: regulation of neurogenesis evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Phylogenetic annotation reflecting Hairy's role in the peripheral nervous system, where it regulates sensory organ precursor selection by repressing proneural genes. action: ACCEPT reason: 'Directly supported experimentally: Hairy represses the proneural gene achaete, controlling adult bristle (sensory organ) patterning.' supported_by: - reference_id: PMID:7958929 supporting_text: direct downstream target of h regulation in vivo - term: id: GO:0000978 label: RNA polymerase II cis-regulatory region sequence-specific DNA binding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: Phylogenetic annotation of sequence-specific binding to Pol II cis-regulatory regions, matching Hairy's direct binding of target promoters/enhancers. action: ACCEPT reason: Hairy binds specific sites (N-box/class-C sites) in target cis-regulatory regions; corroborated by IDA from PMID:7958929. supported_by: - reference_id: PMID:7958929 supporting_text: DNA-binding protein and transcriptional repressor - term: id: GO:0003677 label: DNA binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: InterPro-based electronic annotation of generic DNA binding, consistent with the bHLH DNA-binding domain. action: ACCEPT reason: 'Broad but correct; Hairy is a demonstrated sequence-specific DNA-binding protein. A more informative sequence-specific child term is separately annotated.' - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: UniProt subcellular-location electronic annotation to the nucleus. action: ACCEPT reason: Consistent with Hairy's function as a nuclear DNA-binding transcriptional repressor and with the IBA/IC nucleus annotations. - term: id: GO:0006355 label: regulation of DNA-templated transcription evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: InterPro-based electronic annotation of transcriptional regulation, a broad parent of Hairy's repressor activity. action: ACCEPT reason: 'Correct but general; Hairy is specifically a negative regulator (repressor), captured by more specific terms in this set. The broad IEA is retained as acceptable.' - term: id: GO:0046983 label: protein dimerization activity evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: InterPro electronic annotation of dimerization activity, inferred from the bHLH domain that mediates helix-loop-helix dimerization. action: ACCEPT reason: 'Defensible at the family level (bHLH-O proteins dimerize via the HLH domain). Note that Hairy does not promiscuously heterodimerize with class I/II bHLH proteins (PMID:9371806 reports Hairy displays no interactions with any of the HLH proteins tested), so the activity is best understood as homodimerization/family-level rather than broad bHLH heterodimerization; the broad IEA is retained.' - term: id: GO:1990837 label: sequence-specific double-stranded DNA binding evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: enables review: summary: ARBA machine-learning electronic annotation of sequence-specific double-stranded DNA binding. action: ACCEPT reason: Consistent with experimentally demonstrated sequence-specific DNA binding by Hairy (PMID:7958929). supported_by: - reference_id: PMID:7958929 supporting_text: DNA-binding protein and transcriptional repressor - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:14871887 qualifier: enables review: summary: 'IPI annotation from the Topors study. The interacting partner, dTopors, is a RING-finger ubiquitin-protein ligase that binds the basic region of Hairy and mediates its polyubiquitination.' action: MODIFY reason: 'Bare protein binding is uninformative. The identified partner is the E3 ubiquitin ligase Topors, so ubiquitin protein ligase binding is the informative molecular function.' proposed_replacement_terms: - id: GO:0031625 label: ubiquitin protein ligase binding supported_by: - reference_id: PMID:14871887 supporting_text: binds specifically to the basic region of Hairy - reference_id: PMID:14871887 supporting_text: dTopors mediates Hairy polyubiquitination - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:16455680 qualifier: enables review: summary: 'IPI from a Hox interactome screen showing a physical interaction between Hairy and the Hox protein Ultrabithorax (UBX).' action: MODIFY reason: 'Bare protein binding is uninformative, and the partner is curated input data: the GOA row carries WITH/FROM = UniProtKB:P83949, resolved by the fetched UniProt record as Ubx (hairy-uniprot.txt:131, ''P14003; P83949: Ubx''). Ultrabithorax is a Hox homeodomain sequence-specific DNA-binding transcription factor, so GO:0140297 DNA-binding transcription factor binding is the informative term - the same WITH/FROM-driven treatment applied to every other GO:0005515 IPI row in this file (GO:0031625 for the Topors and Degringolade rows, GO:0001222 for the Groucho and CtBP rows). The interaction is peripheral and context-specific rather than part of Hairy''s core repressor mechanism, so it should not be treated as a core function, but that belongs in the reason rather than in retaining a bare uninformative term.' proposed_replacement_terms: - id: GO:0140297 label: DNA-binding transcription factor binding supported_by: - reference_id: PMID:16455680 supporting_text: Interactions were confirmed with wild-type Ultrabithorax (UBX) in phage display - reference_id: PMID:16455680 supporting_text: pupal death phenotype induced by ectopic expression of the UBX partner Hairy - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17898168 qualifier: enables review: summary: 'IPI from the dMyc-Groucho study; the curated partner is Groucho (isoform 2).' action: MODIFY reason: 'Bare protein binding is uninformative, and the partner is not unverifiable: the GOA row carries WITH/FROM = UniProtKB:P16371-2, resolved by the fetched UniProt record as Groucho isoform 2 (hairy-uniprot.txt:129, ''P14003; P16371-2: gro''). The cached record is abstract-only, but partner identity is curated input data rather than something that has to be recovered from the abstract, so the unverifiable-evidence policy does not apply. Groucho is a transcriptional corepressor and Hairy-Groucho recruitment via the WRPW motif is this protein''s canonical repression mechanism, already captured at GO:0001222 on the PMID:10433905, PMID:8649374, PMID:9371806 and PMID:9892668 rows; assign the same term here for consistency.' proposed_replacement_terms: - id: GO:0001222 label: transcription corepressor binding supported_by: - reference_id: UniProtKB:P14003 supporting_text: Interacts with gro (via WPRW motif) - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19805071 qualifier: enables review: summary: 'IPI from the Knirps-Groucho short-range repression study; the curated partner for the Hairy row is Groucho.' action: MODIFY reason: 'Bare protein binding is uninformative, and the partner underlying this IPI is stated rather than unconfirmable: the GOA row carries WITH/FROM = UniProtKB:P16371, resolved by the fetched UniProt record as Groucho (hairy-uniprot.txt:128, ''P14003; P16371: gro''). Although the paper''s headline result concerns Knirps, curated partner identity is input data, not an inference from the text, and Hairy-Groucho is the canonical WRPW-motif corepressor interaction annotated at GO:0001222 elsewhere in this file. Assign transcription corepressor binding.' proposed_replacement_terms: - id: GO:0001222 label: transcription corepressor binding supported_by: - reference_id: UniProtKB:P14003 supporting_text: Interacts with gro (via WPRW motif) - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21343912 qualifier: enables review: summary: 'IPI from the Degringolade (Dgrn) study. Dgrn is a RING-finger/SUMO-targeted ubiquitin ligase that binds and ubiquitinates Hairy to inhibit Groucho recruitment. This stub collapses three GOA rows from this reference, whose WITH/FROM accessions are UniProtKB:Q9VNJ0 (dgrn), UniProtKB:O46036 (CtBP) and UniProtKB:P16371 (gro).' action: MODIFY reason: 'Bare protein binding is uninformative. Of the three partners this reference contributes, Degringolade is an E3 ubiquitin ligase, so ubiquitin protein ligase binding is the informative molecular function for that row; CtBP and Groucho are transcriptional corepressors, so transcription corepressor binding is needed alongside it to cover the other two rows (all three accessions read off the GOA WITH/FROM column and confirmed against hairy-uniprot.txt:126-128).' proposed_replacement_terms: - id: GO:0031625 label: ubiquitin protein ligase binding - id: GO:0001222 label: transcription corepressor binding supported_by: - reference_id: PMID:21343912 supporting_text: Dgrn is a negative regulator of the repressor Hairy and its corepressor Groucho - reference_id: PMID:21343912 supporting_text: it targets Hairy for SUMO-independent ubiquitylation that inhibits the recruitment of its corepressor Gro - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:9371806 qualifier: enables review: summary: 'Yeast two-hybrid neural-fate network study directly demonstrating that Hairy interacts with the corepressor Groucho (and not with the tested proneural/E(spl)/Da bHLH proteins).' action: MODIFY reason: 'Bare protein binding is uninformative. The demonstrated partner is the transcriptional corepressor Groucho, so transcription corepressor binding is the informative MF.' proposed_replacement_terms: - id: GO:0001222 label: transcription corepressor binding supported_by: - reference_id: PMID:9371806 supporting_text: It does interact with the non-HLH protein Groucho - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:9524128 qualifier: enables review: summary: 'IPI identifying dCtBP as a direct Hairy-interacting protein binding a small C-terminal region of Hairy and required for Hairy-mediated repression and embryonic segmentation.' action: MODIFY reason: 'Bare protein binding is uninformative. The partner CtBP is a transcriptional corepressor, so transcription corepressor binding is the informative MF.' proposed_replacement_terms: - id: GO:0001222 label: transcription corepressor binding supported_by: - reference_id: PMID:9524128 supporting_text: dCtBP interacts - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:9892668 qualifier: enables review: summary: 'IPI from the Groucho/dCtBP repression-pathway study; Hairy is one of the long-range repressors that recruit the Groucho corepressor.' action: MODIFY reason: 'Bare protein binding is uninformative. The functionally dominant partner is the Groucho corepressor, so transcription corepressor binding is the informative MF.' proposed_replacement_terms: - id: GO:0001222 label: transcription corepressor binding supported_by: - reference_id: PMID:9892668 supporting_text: the two long-range repressors, Hairy and Dorsal, recruit a different corepressor - term: id: GO:0001222 label: transcription corepressor binding evidence_type: IPI original_reference_id: PMID:10433905 qualifier: enables review: summary: 'Transcription corepressor binding, reflecting Hairy''s recruitment of Groucho through its WRPW motif (the Huckebein study establishes the shared WRPW/FRPW Groucho-recruitment paradigm for Hairy-related repressors).' action: ACCEPT reason: 'This is an informative molecular function capturing the core repression mechanism (Groucho recruitment). Retained as a key MF; corroborated by direct Hairy-Groucho interaction data (PMID:9371806, PMID:8649374).' supported_by: - reference_id: PMID:10433905 supporting_text: WRPW Groucho-recruitment domain found in - term: id: GO:0000122 label: negative regulation of transcription by RNA polymerase II evidence_type: IMP original_reference_id: PMID:25569482 qualifier: involved_in review: summary: 'Experimental annotation in which Hairy is used as a WRPW/Groucho-dependent repressor; expression of Hairy represses the Sxl target in embryos.' action: ACCEPT reason: 'Consistent with Hairy''s core function as a negative regulator of Pol II transcription; the study assays Hairy-mediated, WRPW-dependent repression in vivo.' supported_by: - reference_id: PMID:25569482 supporting_text: used to replace the Gro-binding WRPW motif of the Hairy repressor and tested for its ability to repress Sxl expression in the embryo - reference_id: PMID:25569482 supporting_text: Repression depends on the WRPW motif of Hairy - term: id: GO:0000122 label: negative regulation of transcription by RNA polymerase II evidence_type: IDA original_reference_id: PMID:7958929 qualifier: involved_in review: summary: 'Direct demonstration that Hairy is a transcriptional repressor, repressing the proneural gene achaete in vivo. Core function.' action: ACCEPT reason: 'One of the defining experimental results for Hairy: it is a sequence-specific DNA-binding transcriptional repressor of a Pol II target gene.' supported_by: - reference_id: PMID:7958929 supporting_text: hairy is a direct - reference_id: PMID:7958929 supporting_text: transcriptional repressor - term: id: GO:0000978 label: RNA polymerase II cis-regulatory region sequence-specific DNA binding evidence_type: IDA original_reference_id: PMID:7958929 qualifier: enables review: summary: 'Direct demonstration that Hairy is a sequence-specific DNA-binding protein recognizing a defined high-affinity site in the achaete cis-regulatory region.' action: ACCEPT reason: Core DNA-binding function; a single conserved high-affinity Hairy site upstream of achaete is required for repression in vivo. supported_by: - reference_id: PMID:7958929 supporting_text: direct downstream target of h regulation in vivo - term: id: GO:0001227 label: DNA-binding transcription repressor activity, RNA polymerase II-specific evidence_type: IDA original_reference_id: PMID:7958929 qualifier: enables review: summary: 'Direct experimental annotation of Hairy as a sequence-specific DNA-binding Pol II transcriptional repressor. This is the most informative molecular-function term for Hairy.' action: ACCEPT reason: Precisely captures Hairy's core molecular function as an active, sequence-specific DNA-binding repressor of Pol II transcription. supported_by: - reference_id: PMID:7958929 supporting_text: DNA-binding protein and transcriptional repressor - reference_id: PMID:7958929 supporting_text: transcriptional repressor - term: id: GO:0070888 label: E-box binding evidence_type: IDA original_reference_id: PMID:7958929 qualifier: enables review: summary: 'FlyBase IDA of E-box binding. Hairy binds a defined high-affinity site in the achaete regulatory region; the Hairy-class recognition site is a class-C/N-box-type element.' action: ACCEPT reason: 'Retained as an experimental (IDA) binding-specificity annotation, deferring to the curator who read the full text. Note that UniProt records a preference of Hairy''s proline-interrupted basic region for the N-box (CACNAG) over the canonical E-box (CANNTG); the E-box and N-box/class-C annotations both reflect genuine sequence-specific binding and are not contradictory.' supported_by: - reference_id: PMID:7958929 supporting_text: DNA-binding protein and transcriptional repressor - term: id: GO:0000902 label: cell morphogenesis evidence_type: IMP original_reference_id: PMID:12526813 qualifier: involved_in review: summary: 'IMP from a new hairy allele causing salivary tube shape defects. The effect is indirect, mediated by failure to repress huckebein.' action: KEEP_AS_NON_CORE reason: 'Genuine mutant phenotype but a downstream morphogenetic consequence of loss of Hairy''s transcriptional repression (via prolonged huckebein expression), not a distinct core function of this nuclear repressor. Retained as non-core.' supported_by: - reference_id: PMID:12526813 supporting_text: hairy mutations cause branching and bulging of the normally - reference_id: PMID:12526813 supporting_text: prolonged expression of huckebein - term: id: GO:0007435 label: salivary gland morphogenesis evidence_type: IMP original_reference_id: PMID:12526813 qualifier: involved_in review: summary: 'IMP: hairy mutations cause branching/bulging of the salivary tube via prolonged huckebein expression.' action: KEEP_AS_NON_CORE reason: Pleiotropic developmental role that is an indirect consequence of loss of Hairy-mediated repression of huckebein; retained as non-core rather than a core function. supported_by: - reference_id: PMID:12526813 supporting_text: hairy mutations cause branching and bulging of the normally - term: id: GO:0007435 label: salivary gland morphogenesis evidence_type: IGI original_reference_id: PMID:12526813 qualifier: involved_in review: summary: 'Genetic-interaction evidence (IGI) for the same salivary-gland role, consistent with the hairy-huckebein-crumbs/klarsicht regulatory relationships described in the study.' action: KEEP_AS_NON_CORE reason: Corroborates the salivary gland role via genetic interactions; still an indirect, pleiotropic developmental role and retained as non-core. supported_by: - reference_id: PMID:12526813 supporting_text: prolonged expression of huckebein - term: id: GO:0035239 label: tube morphogenesis evidence_type: IMP original_reference_id: PMID:12526813 qualifier: involved_in review: summary: 'IMP for the broader tube-morphogenesis process, reflecting the salivary tube shape defects of hairy mutants.' action: KEEP_AS_NON_CORE reason: Broader parent of the salivary-gland phenotype; an indirect consequence of loss of Hairy repression and retained as non-core. supported_by: - reference_id: PMID:12526813 supporting_text: hairy mutations cause branching and bulging of the normally - term: id: GO:0045892 label: negative regulation of DNA-templated transcription evidence_type: IDA original_reference_id: PMID:7768186 qualifier: involved_in review: summary: 'Direct evidence that Hairy represses the pair-rule gene fushi tarazu (ftz) through a defined fDE1 element during blastoderm segmentation.' action: ACCEPT reason: Supports Hairy's core repressor function in embryonic segmentation; ftz reporter expression depends on activation by runt and repression by hairy. supported_by: - reference_id: PMID:7768186 supporting_text: runt and hairy are required for the proper - reference_id: PMID:7768186 supporting_text: repression by hairy - term: id: GO:0001666 label: response to hypoxia evidence_type: IMP original_reference_id: PMID:18927626 qualifier: involved_in review: summary: 'IMP from hypoxia-tolerance selection experiments; hairy is up-regulated in tolerant flies and acts as a metabolic switch repressing metabolic genes, and hairy mutations reduce hypoxia tolerance.' action: KEEP_AS_NON_CORE reason: 'Genuine but context-specific, pleiotropic role in which Hairy''s repressor activity is deployed on metabolic target genes; retained as a non-core biological process.' supported_by: - reference_id: PMID:18927626 supporting_text: The transcriptional suppressor, hairy, was up-regulated - reference_id: PMID:18927626 supporting_text: hairy acting as a metabolic switch - term: id: GO:0000122 label: negative regulation of transcription by RNA polymerase II evidence_type: IDA original_reference_id: PMID:8649374 qualifier: involved_in review: summary: 'Direct demonstration that Hairy-related repressors actively repress transcription via the WRPW motif recruiting Groucho/TLE corepressors to target promoters.' action: ACCEPT reason: Core repressor function; the WRPW motif is shown to be a sufficient active repression domain that recruits Groucho. supported_by: - reference_id: PMID:8649374 supporting_text: recruited by the 4-amino acid protein-protein interaction domain, WRPW - term: id: GO:0003677 label: DNA binding evidence_type: IDA original_reference_id: PMID:8649374 qualifier: enables review: summary: 'DNA binding annotation; Hairy-related proteins are defined as site-specific DNA-binding proteins with a repressor-specific bHLH domain.' action: ACCEPT reason: Consistent with Hairy's demonstrated sequence-specific DNA binding; broad but correct. supported_by: - reference_id: PMID:8649374 supporting_text: presence of both a repressor-specific bHLH DNA binding domain and a - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:8649374 qualifier: enables review: summary: 'IPI reflecting the Hairy-Groucho interaction mediated by the WRPW motif, shown to recruit Groucho/TLE corepressors to promoters.' action: MODIFY reason: 'Bare protein binding is uninformative. The partner recruited by the WRPW motif is the Groucho corepressor, so transcription corepressor binding is the informative MF.' proposed_replacement_terms: - id: GO:0001222 label: transcription corepressor binding supported_by: - reference_id: PMID:8649374 supporting_text: recruited by the 4-amino acid protein-protein interaction domain, WRPW - term: id: GO:0005634 label: nucleus evidence_type: IC original_reference_id: PMID:8649374 qualifier: located_in review: summary: 'Curator-inferred (IC) nuclear localization, consistent with Hairy acting as a promoter-bound DNA-binding repressor that recruits Groucho.' action: ACCEPT reason: Consistent with Hairy's nuclear DNA-binding transcriptional-repressor function and other nucleus annotations in this set. - term: id: GO:0045892 label: negative regulation of DNA-templated transcription evidence_type: IDA original_reference_id: PMID:8649374 qualifier: involved_in review: summary: 'Direct evidence of active transcriptional repression by Hairy-related proteins via the WRPW/Groucho mechanism.' action: ACCEPT reason: Supports the core repressor function at the DNA-templated-transcription level; WRPW is a sufficient active repression domain. supported_by: - reference_id: PMID:8649374 supporting_text: recruited by the 4-amino acid protein-protein interaction domain, WRPW - term: id: GO:0007424 label: open tracheal system development evidence_type: IMP original_reference_id: PMID:15848387 qualifier: involved_in review: summary: 'IMP for a role in tracheal development. The cited paper is an EMS tracheal mutagenesis screen; the cached full text (available) foregrounds btl, pointed, and kni/knrl and does not mention hairy.' action: UNDECIDED reason: 'The supporting evidence for a hairy tracheal role cannot be verified from the cached full text (zero occurrences of the gene name), and the specific complementation group is not named in the available text. Following curation policy for unverifiable experimental annotations, this is marked UNDECIDED rather than accepted or removed.' - term: id: GO:0061024 label: membrane organization evidence_type: TAS original_reference_id: PMID:12593813 qualifier: involved_in review: summary: 'TAS annotation traced to a Current Biology dispatch on tubular-organ lumen size and intracellular vesicle transport.' action: MARK_AS_OVER_ANNOTATED reason: 'Hairy is a sequence-specific nuclear transcriptional repressor; membrane organization is a distal phenotypic consequence (apical-membrane growth during salivary tube morphogenesis, itself downstream of huckebein derepression) rather than a molecular or cellular function of Hairy. The reference is a review dispatch that does not describe a Hairy function. Flagged as an over-annotation.' - term: id: GO:0000122 label: negative regulation of transcription by RNA polymerase II evidence_type: IMP original_reference_id: PMID:9892668 qualifier: involved_in review: summary: 'IMP from transgenic misexpression of wild-type and mutant Hairy showing that Hairy-mediated repression in the embryo depends on the WRPW/Groucho interaction.' action: ACCEPT reason: Supports the core repressor function; Hairy repression in vivo requires the Groucho-recruitment (WRPW) sequence. supported_by: - reference_id: PMID:9892668 supporting_text: Hairy-mediated - term: id: GO:0000122 label: negative regulation of transcription by RNA polymerase II evidence_type: IPI original_reference_id: PMID:9892668 qualifier: involved_in review: summary: 'Annotation linking Hairy''s negative regulation of transcription to its physical recruitment of the Groucho corepressor (the two long-range repressors Hairy and Dorsal recruit Groucho).' action: ACCEPT reason: Consistent with the core repressor function; Hairy-mediated repression is Groucho-dependent. supported_by: - reference_id: PMID:9892668 supporting_text: the two long-range repressors, Hairy and Dorsal, recruit a different corepressor - term: id: GO:0007366 label: periodic partitioning by pair rule gene evidence_type: TAS original_reference_id: PMID:10611687 qualifier: involved_in review: summary: 'TAS annotation of Hairy''s canonical role as a pair-rule gene contributing to periodic (segmental) partitioning of the embryo.' action: ACCEPT reason: 'Hairy is a primary pair-rule segmentation gene; periodic partitioning by pair-rule gene is a precise, core segmentation process. Supported by primary literature establishing Hairy as a pair-rule repressor.' supported_by: - reference_id: PMID:9524128 supporting_text: hairy is a Drosophila pair-rule segmentation gene that functions genetically as - term: id: GO:0007366 label: periodic partitioning by pair rule gene evidence_type: TAS original_reference_id: PMID:15382142 qualifier: involved_in review: summary: 'TAS annotation (arthropod-segmentation review) placing Hairy among the primary pair-rule genes contributing to periodic segmental partitioning.' action: ACCEPT reason: Core segmentation role, consistent with Hairy being one of the primary pair-rule genes of Drosophila. supported_by: - reference_id: PMID:15382142 supporting_text: primary pair-rule genes of Drosophila - term: id: GO:0007399 label: nervous system development evidence_type: TAS original_reference_id: PMID:12815726 qualifier: involved_in review: summary: 'Broad TAS annotation of nervous system development, traced to a review of HLH gene classes in neural development.' action: KEEP_AS_NON_CORE reason: 'Hairy does function in nervous-system (bristle/SOP) patterning via repression of proneural genes, so the broad term is not wrong; however it is a very general parent captured more precisely by regulation of neurogenesis, and the cited reference is a generic HLH-class review rather than a Hairy study. Retained as non-core.' additional_reference_ids: - PMID:7958929 supported_by: - reference_id: PMID:7958929 supporting_text: negative regulator in both embryonic segmentation and adult - term: id: GO:0035289 label: posterior head segmentation evidence_type: TAS original_reference_id: PMID:15382142 qualifier: involved_in review: summary: 'TAS annotation of a role in posterior head segmentation, within Hairy''s pair-rule segmentation function.' action: ACCEPT reason: Consistent with Hairy's pair-rule segmentation role; retained as part of the core segmentation function. supported_by: - reference_id: PMID:15382142 supporting_text: primary pair-rule genes of Drosophila - term: id: GO:0035290 label: trunk segmentation evidence_type: TAS original_reference_id: PMID:15382142 qualifier: involved_in review: summary: 'TAS annotation of trunk segmentation, the principal segmental domain patterned by the pair-rule gene Hairy.' action: ACCEPT reason: Core segmentation process; Hairy is a primary pair-rule gene patterning the trunk. supported_by: - reference_id: PMID:15382142 supporting_text: primary pair-rule genes of Drosophila core_functions: - description: Sequence-specific DNA-binding transcriptional repressor of the bHLH-Orange (HES) family; binds N-box/class-C sites in target cis-regulatory regions through a repressor-type bHLH domain and actively represses RNA polymerase II transcription of target genes such as achaete and fushi tarazu. supported_by: - reference_id: PMID:7958929 supporting_text: transcriptional repressor - reference_id: PMID:7958929 supporting_text: direct downstream target of h regulation in vivo 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 - id: GO:0007366 label: periodic partitioning by pair rule gene - id: GO:0050767 label: regulation of neurogenesis locations: - id: GO:0005634 label: nucleus - description: Recruits the Groucho (Gro/TLE) transcriptional corepressor to target promoters via its C-terminal WRPW tetrapeptide, converting DNA-bound Hairy into an active long-range repressor complex; the corepressor-recruitment activity is the mechanistic basis of Hairy-mediated repression. supported_by: - reference_id: PMID:8649374 supporting_text: recruited by the 4-amino acid protein-protein interaction domain, WRPW - reference_id: PMID:9371806 supporting_text: It does interact with the non-HLH protein Groucho molecular_function: id: GO:0001222 label: transcription corepressor binding directly_involved_in: - id: GO:0000122 label: negative regulation of transcription by RNA polymerase II locations: - id: GO:0005634 label: nucleus proposed_new_terms: [] suggested_questions: - question: >- To what extent does Hairy repress through the N-box (CACNAG) versus E-box/class-C sites genome-wide, and does binding-site type correlate with distinct target-gene classes (segmentation vs. proneural vs. metabolic)? - question: >- How is the balance between Groucho- and CtBP-dependent repression by Hairy set at individual target loci, given the evidence that the two corepressors act through separate, sometimes antagonistic, pathways? suggested_experiments: - description: >- Genome-wide binding (CUT&RUN or ChIP-seq) of Hairy in staged embryos combined with motif analysis to quantify N-box vs. E-box occupancy and integrate with target-gene expression. - description: >- Structure-function dissection separating the WRPW/Groucho and PLSLV/CtBP interaction surfaces (point mutants) with transcriptional readouts at segmentation and proneural targets to define corepressor-specific target sets. references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: UniProtKB:P14003 title: 'UniProtKB P14003 (HAIR_DROME): Protein hairy' findings: - statement: Hairy represses transcription by forming a complex with the Groucho corepressor, recruited through its C-terminal WRPW motif. supporting_text: Interacts with gro (via WPRW motif) reference_review: relevance: HIGH correctness: VERIFIED review_notes: UniProt record for P14003. Its SUBUNIT block records the gro (Groucho) and Topors interactions and its INTERACTION block resolves the WITH/FROM accessions carried by the GOA protein-binding rows, which is what anchors the corepressor-binding MODIFY calls on the IPI annotations whose cached papers do not themselves name the partner. - id: PMID:10433905 title: Huckebein repressor activity in Drosophila terminal patterning is mediated by Groucho. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: 'Abstract-only cache verified against PubMed. Concerns Huckebein but establishes the shared WRPW/FRPW Groucho-recruitment paradigm for Hairy-related repressors; supports Hairy''s transcription corepressor (Groucho) binding at the family level.' - id: PMID:10611687 title: The origin and evolution of segmentation. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: General review on the evolution of segmentation used as a TAS source for the pair-rule/periodic-partitioning role; does not itself describe Hairy specifics. - id: PMID:12526813 title: Epithelial tube morphology is determined by the polarized growth and delivery of apical membrane. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: 'Abstract-only cache verified; a new hairy allele causes salivary tube branching/bulging via prolonged huckebein expression. Supports non-core salivary/tube morphogenesis roles (indirect, via loss of Hairy repression).' - id: PMID:12593813 title: 'Tube morphogenesis: no pipe dream in Drosophila.' findings: [] reference_review: relevance: LOW correctness: MISCITED review_notes: 'Current Biology dispatch on tube lumen size and vesicle transport; does not describe a Hairy molecular function. Basis of the over-annotated membrane organization TAS for Hairy.' - id: PMID:12815726 title: The role of class I HLH genes in neural development--have they been overlooked? findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Generic review of HLH classes in neural development; a weak TAS source for the broad nervous system development annotation. Hairy's neural role is better supported by PMID:7958929. - id: PMID:14871887 title: Drosophila Topors is a RING finger-containing protein that functions as a ubiquitin-protein isopeptide ligase for the hairy basic helix-loop-helix repressor protein. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: 'Directly on Hairy: dTopors binds the basic region of Hairy and mediates its polyubiquitination, antagonizing repression. Supports MODIFY of a bare protein-binding IPI to ubiquitin protein ligase binding.' - id: PMID:15382142 title: The evolution of arthropod segmentation mechanisms. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Review grouping Hairy among the primary pair-rule genes of Drosophila; TAS source for periodic partitioning, trunk, and posterior-head segmentation. - id: PMID:15848387 title: A molecular link between FGF and Dpp signaling in branch-specific migration of the Drosophila trachea. findings: [] reference_review: relevance: LOW correctness: UNVERIFIED review_notes: 'Cached full text (available) contains zero occurrences of the hairy gene name; foregrounds btl, pointed, kni/knrl. Cannot verify the Hairy tracheal IMP from the cache; annotation left UNDECIDED.' - id: PMID:16455680 title: Physical and genetic interactions link hox function with diverse transcription factors and cell signaling proteins. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: 'Abstract-only cache verified; the abstract names Hairy directly as a UBX partner and states the assays (yeast two-hybrid, phage display confirmation, immunoprecipitation for a subset). The GOA row''s WITH/FROM = UniProtKB:P83949 = Ubx (hairy-uniprot.txt:131) identifies the partner as a Hox homeodomain DNA-binding transcription factor, so the annotation is a MODIFY to GO:0140297. Peripheral to Hairy''s core repressor function, which is recorded in the annotation reason.' - id: PMID:17898168 title: A Myc-Groucho complex integrates EGF and Notch signaling to regulate neural development. findings: [] reference_review: relevance: LOW correctness: UNVERIFIED review_notes: Abstract-only cache concerns the dMyc-Groucho complex and does not name Hairy, hence UNVERIFIED as a statement about the cached text. The partner behind this protein-binding IPI is nonetheless curated input data, since the GOA row carries WITH/FROM = UniProtKB:P16371-2, resolved by the fetched UniProt record as Groucho isoform 2 (hairy-uniprot.txt:129), so the annotation is a MODIFY to GO:0001222 rather than UNDECIDED. - id: PMID:18927626 title: 'Mechanisms underlying hypoxia tolerance in Drosophila melanogaster: hairy as a metabolic switch.' findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: 'Full text available and verified; hairy up-regulated in hypoxia-tolerant flies and acts as a metabolic switch, with hairy mutations reducing tolerance. Supports non-core response-to-hypoxia role.' - id: PMID:19805071 title: Groucho corepressor functions as a cofactor for the Knirps short-range transcriptional repressor. findings: [] reference_review: relevance: LOW correctness: UNVERIFIED review_notes: Full text available; experimental interaction data concern Knirps-Groucho, and Hairy appears only as a long-range-repressor comparison, so the text does not itself document the Hairy interaction. The GOA row supplies the partner as WITH/FROM = UniProtKB:P16371, resolved by the fetched UniProt record as Groucho (hairy-uniprot.txt:128), so the annotation is a MODIFY to GO:0001222 rather than UNDECIDED. - id: PMID:21343912 title: Degringolade, a SUMO-targeted ubiquitin ligase, inhibits Hairy/Groucho-mediated repression. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: 'Directly on Hairy: the E3 ligase Degringolade binds and ubiquitinates Hairy to inhibit Groucho recruitment. Supports MODIFY of a bare protein-binding IPI to ubiquitin protein ligase binding for the dgrn partner, and to transcription corepressor binding for the CtBP and Groucho partners that the same reference contributes as separate GOA rows (WITH/FROM = UniProtKB:O46036 and UniProtKB:P16371).' - id: PMID:25569482 title: Origins of context-dependent gene repression by capicua. findings: [] reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: 'Full text available and verified; uses a Hairy WRPW/Gro-dependent Sxl-repression assay. Supports Hairy''s negative regulation of Pol II transcription.' - id: PMID:7768186 title: 'Pair-rule expression of the Drosophila fushi tarazu gene: a nuclear receptor response element mediates the opposing regulatory effects of runt and hairy.' findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: 'Directly on Hairy: Hairy represses ftz through the fDE1 element during blastoderm segmentation. Supports negative regulation of DNA-templated transcription and the segmentation role.' - id: PMID:7958929 title: 'Negative regulation of proneural gene activity: hairy is a direct transcriptional repressor of achaete.' findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: 'Key primary paper: establishes Hairy as a sequence-specific DNA-binding transcriptional repressor and identifies achaete as a direct in vivo target controlling PNS/bristle patterning.' - id: PMID:8649374 title: The WRPW motif of the hairy-related basic helix-loop-helix repressor proteins acts as a 4-amino-acid transcription repression and protein-protein interaction domain. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: 'Key primary paper: the WRPW motif is a sufficient active repression domain that recruits Groucho/TLE corepressors. Supports the core repression mechanism and corepressor binding.' - id: PMID:9371806 title: A network of interacting transcriptional regulators involved in Drosophila neural fate specification revealed by the yeast two-hybrid system. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: 'Verified; Hairy interacts directly with Groucho but not with the tested proneural/E(spl)/Da bHLH proteins. Supports transcription corepressor binding and informs the dimerization caveat.' - id: PMID:9524128 title: 'Drosophila CtBP: a Hairy-interacting protein required for embryonic segmentation and hairy-mediated transcriptional repression.' findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: 'Directly on Hairy: dCtBP binds a C-terminal region of Hairy and is required for Hairy-mediated repression and segmentation. Supports transcription corepressor binding and the pair-rule role.' - id: PMID:9892668 title: Groucho and dCtBP mediate separate pathways of transcriptional repression in the Drosophila embryo. findings: [] reference_review: relevance: HIGH correctness: VERIFIED review_notes: 'Verified; Hairy-mediated repression in vivo depends on the WRPW/Groucho interaction rather than the weak dCtBP motif. Supports Groucho as the dominant corepressor and the core repressor function.'