Hes7 is a Hairy/Enhancer-of-split-related basic helix-loop-helix (bHLH-Orange) transcriptional repressor carrying a C-terminal WRPW Groucho/TLE-recruitment motif. It is a direct Notch-signalling target expressed specifically and dynamically in the presomitic mesoderm (PSM), where it binds N-box elements in its own promoter and in the Lunatic fringe (Lfng) promoter and represses their transcription. Hes7 protein is extremely short-lived, and this instability together with negative autoregulation generates the ~2-hour oscillation of the mouse somite segmentation clock; Hes7 thereby periodically represses Lfng and other cyclic Notch-pathway genes, providing negative feedback on Notch activity. Loss of Hes7 in mouse disrupts somite segmentation and somite rostro-caudal polarity, producing fused and disorganised vertebrae and ribs and a shortened tail; HES7 missense mutation in human causes spondylocostal dysostosis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000122 negative regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: IBA (PANTHER:PTN004213585, HES/HEY family node) propagating negative regulation of RNA polymerase II transcription. Hes7 is an experimentally established repressor of Pol II promoters (Lfng, Hes7 itself). Reason: Consistent with direct evidence that Hes7 binds N-boxes and represses Lfng and its own promoter; this is the core biological process of a Hes-family repressor. Supporting Evidence: PMID:16342160 Hes7, another cyclically expressed protein, can bind to the N-boxes on both Lfng and its own promoters and repress their activity. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:11260262 Hes7: a bHLH-type repressor gene regulated by Notch and expr... | ACCEPT | Summary: Transfection assays showed Hes7 represses transcription from N-box and E-box promoters and suppresses E47-induced activation. Reason: Direct reporter evidence for Pol II transcriptional repression by Hes7. Supporting Evidence: PMID:11260262 In a transfection analysis, Hes7 represses transcription from the N box- and E box-containing promoters. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:15170214 Instability of Hes7 protein is crucial for the somite segmen... | ACCEPT | Summary: Hirata et al. generated a stabilised Hes7 with normal repressor activity and studied the autorepression loop underlying the segmentation clock. Reason: The paper models and tests direct Hes7 autorepression; the repressor activity is the function under study. Consistent with other direct evidence. Supporting Evidence: PMID:15170214 we generated mice expressing mutant Hes7 with a longer half-life (approximately 30 min compared with approximately 22 min for wild-type Hes7) but normal repressor activity |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:15902259 The Mesp2 transcription factor establishes segmental borders... | ACCEPT | Summary: Morimoto et al. (Mesp2 establishes segment borders by suppressing Notch activity). The cached abstract foregrounds Mesp2/Lfng; the full text (not cached) was read by the MGI curator and presumably includes Hes7 reporter/repression assays. Reason: Cannot verify the specific Hes7 experiment from the abstract, but repression of Pol II transcription by Hes7 is well established by independent evidence; per project policy we defer to the curator rather than overrule an experimental annotation. Supporting Evidence: PMID:16342160 Hes7, another cyclically expressed protein, can bind to the N-boxes on both Lfng and its own promoters and repress their activity. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IGI PMID:21750544 The Wnt3a/Ξ²-catenin target gene Mesogenin1 controls the segm... | ACCEPT | Summary: Genetic interaction with Msgn1: Hes7 blocks the synergistic Msgn1-Notch activation of Lfng and periodically represses Hes7 and Lfng. Reason: Supports Hes7 as the periodic repressor of cyclic Notch-pathway genes. Supporting Evidence: PMID:21750544 Our demonstration that Hes7 blocks the synergistic Msgn1-Notch activation of Lfng is consistent with previous suggestions that Hes7 is the pacemaker |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IDA PMID:16342160 Negative feedback loop formed by Lunatic fringe and Hes7 con... | ACCEPT | Summary: Hes7 binds N-box elements in the Lfng and Hes7 promoters. Reason: Direct DNA-binding evidence at Pol II regulatory regions; core MF component. Supporting Evidence: PMID:16342160 Hes7, another cyclically expressed protein, can bind to the N-boxes on both Lfng and its own promoters and repress their activity. |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA (PANTHER:PTN004213585) for Pol II cis-regulatory sequence-specific DNA binding. Reason: Consistent with direct N-box binding shown for Hes7 (PMID:16342160). Supporting Evidence: PMID:16342160 can bind to the N-boxes on both Lfng and its own promoters |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: IBA (PANTHER:PTN004213585) for Pol II-specific DNA-binding transcription factor activity. Reason: Correct at the family level; the more specific repressor term GO:0001227 is also annotated and is the preferred core MF. Supporting Evidence: PMID:11260262 In a transfection analysis, Hes7 represses transcription from the N box- and E box-containing promoters. |
| GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific | IC GO_REF:0000036 | ACCEPT | Summary: DNA-binding transcription repressor activity, RNA polymerase II-specific. Hes7 binds N-boxes and represses Pol II promoters (Lfng, Hes7); human HES7 disease mutant in the DNA-binding domain loses repression. Reason: This is the core molecular function of Hes7. Supporting Evidence: file:mouse/Hes7/Hes7-deep-research-falcon.md Hes7 functions as a sequence-specific DNA-binding transcriptional repressor that recognizes and binds N-box regulatory sequences in target gene promoters PMID:16342160 Hes7, another cyclically expressed protein, can bind to the N-boxes on both Lfng and its own promoters and repress their activity. PMID:18775957 A missense mutation was identified in the DNA-binding domain of the HES7 protein. |
| GO:0001227 DNA-binding transcription repressor activity, RNA polymerase II-specific | IEA GO_REF:0000117 | ACCEPT | Summary: DNA-binding transcription repressor activity, RNA polymerase II-specific. Hes7 binds N-boxes and represses Pol II promoters (Lfng, Hes7); human HES7 disease mutant in the DNA-binding domain loses repression. Reason: This is the core molecular function of Hes7. Supporting Evidence: file:mouse/Hes7/Hes7-deep-research-falcon.md Hes7 functions as a sequence-specific DNA-binding transcriptional repressor that recognizes and binds N-box regulatory sequences in target gene promoters PMID:16342160 Hes7, another cyclically expressed protein, can bind to the N-boxes on both Lfng and its own promoters and repress their activity. PMID:18775957 A missense mutation was identified in the DNA-binding domain of the HES7 protein. |
| GO:0001501 skeletal system development | IMP PMID:11641270 Dynamic expression and essential functions of Hes7 in somite... | KEEP AS NON CORE | Summary: Hes7-null mice have severely disorganised vertebrae and ribs. Reason: Skeletal defects are a downstream consequence of defective somite segmentation, not a direct role of Hes7 in skeletal development. Supporting Evidence: PMID:11641270 As a result, the somite derivatives such as vertebrae and ribs are severely disorganized. |
| GO:0001756 somitogenesis | IMP PMID:11641270 Dynamic expression and essential functions of Hes7 in somite... | ACCEPT | Summary: Hes7 loss (null allele) or stabilisation disrupts somite segmentation; Hes7 is the core negative-feedback oscillator of the mouse segmentation clock. Reason: Somitogenesis is the principal biological process in which Hes7 acts; supported by multiple independent mouse alleles. Supporting Evidence: PMID:11641270 In Hes7-null mice, somites are not properly segmented and their anterior-posterior polarity is disrupted. PMID:15170214 instability of Hes7 is essential for sustained oscillation and for its function as a segmentation clock. PMID:19779553 Thus, in the absence of Lfng or Hes7 the process of somitogenesis is not properly regulated. |
| GO:0001756 somitogenesis | IMP PMID:15170214 Instability of Hes7 protein is crucial for the somite segmen... | ACCEPT | Summary: Hes7 loss (null allele) or stabilisation disrupts somite segmentation; Hes7 is the core negative-feedback oscillator of the mouse segmentation clock. Reason: Somitogenesis is the principal biological process in which Hes7 acts; supported by multiple independent mouse alleles. Supporting Evidence: PMID:11641270 In Hes7-null mice, somites are not properly segmented and their anterior-posterior polarity is disrupted. PMID:15170214 instability of Hes7 is essential for sustained oscillation and for its function as a segmentation clock. PMID:19779553 Thus, in the absence of Lfng or Hes7 the process of somitogenesis is not properly regulated. |
| GO:0001756 somitogenesis | IMP PMID:15170214 Instability of Hes7 protein is crucial for the somite segmen... | ACCEPT | Summary: Hes7 loss (null allele) or stabilisation disrupts somite segmentation; Hes7 is the core negative-feedback oscillator of the mouse segmentation clock. Reason: Somitogenesis is the principal biological process in which Hes7 acts; supported by multiple independent mouse alleles. Supporting Evidence: PMID:11641270 In Hes7-null mice, somites are not properly segmented and their anterior-posterior polarity is disrupted. PMID:15170214 instability of Hes7 is essential for sustained oscillation and for its function as a segmentation clock. PMID:19779553 Thus, in the absence of Lfng or Hes7 the process of somitogenesis is not properly regulated. |
| GO:0001756 somitogenesis | IMP PMID:19779553 Notch is a critical component of the mouse somitogenesis osc... | ACCEPT | Summary: Hes7 loss (null allele) or stabilisation disrupts somite segmentation; Hes7 is the core negative-feedback oscillator of the mouse segmentation clock. Reason: Somitogenesis is the principal biological process in which Hes7 acts; supported by multiple independent mouse alleles. Supporting Evidence: PMID:11641270 In Hes7-null mice, somites are not properly segmented and their anterior-posterior polarity is disrupted. PMID:15170214 instability of Hes7 is essential for sustained oscillation and for its function as a segmentation clock. PMID:19779553 Thus, in the absence of Lfng or Hes7 the process of somitogenesis is not properly regulated. |
| GO:0003677 DNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based DNA binding (Orange domain IPR003650). Reason: Broad but correct; more specific sequence-specific DNA binding terms are also present. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Nuclear localisation of a DNA-binding transcriptional repressor. Reason: Consistent with its function as a DNA-binding repressor; UniProt location Nucleus. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Nuclear localisation of a DNA-binding transcriptional repressor. Reason: Consistent with its function as a DNA-binding repressor; UniProt location Nucleus. |
| GO:0005654 nucleoplasm | TAS Reactome:R-MMU-9824230 | ACCEPT | Summary: Reactome TAS placing Hes7 in the nucleoplasm (Hes7 binding the Lfng and Hes7 genes). Reason: Appropriate location for a promoter-bound repressor. Supporting Evidence: Reactome:R-MMU-9824230 The Hairy and enhancer of split 7 (Hes7) protein binds 4 N-boxes in the promoter of the Lunatic fringe (Lfng) gene and represses activation of Lfng by Notch signaling |
| GO:0005654 nucleoplasm | TAS Reactome:R-MMU-9824253 | ACCEPT | Summary: Reactome TAS placing Hes7 in the nucleoplasm (Hes7 binding the Lfng and Hes7 genes). Reason: Appropriate location for a promoter-bound repressor. Supporting Evidence: Reactome:R-MMU-9824230 The Hairy and enhancer of split 7 (Hes7) protein binds 4 N-boxes in the promoter of the Lunatic fringe (Lfng) gene and represses activation of Lfng by Notch signaling |
| GO:0005654 nucleoplasm | TAS Reactome:R-MMU-9824278 | ACCEPT | Summary: Reactome TAS placing Hes7 in the nucleoplasm (Hes7 binding the Lfng and Hes7 genes). Reason: Appropriate location for a promoter-bound repressor. Supporting Evidence: Reactome:R-MMU-9824230 The Hairy and enhancer of split 7 (Hes7) protein binds 4 N-boxes in the promoter of the Lunatic fringe (Lfng) gene and represses activation of Lfng by Notch signaling |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based regulation of DNA-templated transcription. Reason: Correct but general; negative regulation of Pol II transcription is the specific process. |
| GO:0007219 Notch signaling pathway | IDA PMID:11260262 Hes7: a bHLH-type repressor gene regulated by Notch and expr... | ACCEPT | Summary: Hes7 expression is controlled by Notch signalling; Hes7 is a Notch target/effector repressor that feeds back on cyclic Notch-pathway genes (Lfng). Reason: As a direct Notch target transcription factor mediating the transcriptional output of the pathway in PSM, Hes7 participates in Notch signalling in the same sense as other Hes effectors; its pathway role is "target TF / negative feedback". Supporting Evidence: PMID:11260262 Promoter analysis indicated that Hes7 expression is controlled by Notch signalling. PMID:18775957 HES7 encodes a bHLH-Orange domain transcriptional repressor protein that is both a direct target of the Notch signaling pathway, and part of a negative feedback mechanism required to attenuate Notch signaling. |
| GO:0009952 anterior/posterior pattern specification | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA (PANTHER:PTN000105428) anterior/posterior pattern specification. Hes7 nulls lose somite anterior-posterior (rostro-caudal) polarity. Reason: Supported for Hes7 via its somite polarity phenotype, but this is a consequence of its clock role rather than a primary function. Supporting Evidence: PMID:11641270 In Hes7-null mice, somites are not properly segmented and their anterior-posterior polarity is disrupted. |
| GO:0036342 post-anal tail morphogenesis | IMP PMID:11641270 Dynamic expression and essential functions of Hes7 in somite... | KEEP AS NON CORE | Summary: Hes7-null mice have shortened tails and heterozygotes frequently have kinked tails. Reason: Tail defects are a consequence of defective segmentation of the axial skeleton. Supporting Evidence: PMID:11641270 suggesting that the dose of Hes7 gene is important for normal tail structure. |
| GO:0045892 negative regulation of DNA-templated transcription | IDA PMID:12783854 Periodic repression by the bHLH factor Hes7 is an essential ... | ACCEPT | Summary: Hes7 protein periodically represses Hes7 and Lfng transcription; in the human paper the SCD mutant loses repression. Reason: Correct; parent of GO:0000122, consistent with direct evidence. Supporting Evidence: PMID:12783854 periodic repression by Hes7 protein is critical for the cyclic transcription of Hes7 and Lfng |
| GO:0045892 negative regulation of DNA-templated transcription | IDA PMID:18775957 Mutation of Hairy-and-Enhancer-of-Split-7 in humans causes s... | ACCEPT | Summary: Hes7 protein periodically represses Hes7 and Lfng transcription; in the human paper the SCD mutant loses repression. Reason: Correct; parent of GO:0000122, consistent with direct evidence. Supporting Evidence: PMID:12783854 periodic repression by Hes7 protein is critical for the cyclic transcription of Hes7 and Lfng |
| GO:0046983 protein dimerization activity | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-derived protein dimerization activity from the bHLH/HLH domain. Reason: bHLH factors act as dimers, so this is correct, but it is a generic structural property and not specifically characterised for mouse Hes7 in the cached literature. |
| GO:0048511 rhythmic process | IDA PMID:11641270 Dynamic expression and essential functions of Hes7 in somite... | ACCEPT | Summary: Hes7 mRNA and protein oscillate with a ~2-h period in the PSM (segmentation clock). Reason: Hes7 is itself a component of the oscillator (negative autoregulatory loop), so it directly participates in this rhythmic process. The term is broad; no specific segmentation-clock GO term exists. Supporting Evidence: PMID:11641270 Here, we found that Hes7 expression oscillates in 2-h cycles in the presomitic mesoderm (PSM). PMID:15170214 instability of Hes7 is essential for sustained oscillation and for its function as a segmentation clock. |
| GO:0048511 rhythmic process | IMP PMID:15170214 Instability of Hes7 protein is crucial for the somite segmen... | ACCEPT | Summary: Hes7 mRNA and protein oscillate with a ~2-h period in the PSM (segmentation clock). Reason: Hes7 is itself a component of the oscillator (negative autoregulatory loop), so it directly participates in this rhythmic process. The term is broad; no specific segmentation-clock GO term exists. Supporting Evidence: PMID:11641270 Here, we found that Hes7 expression oscillates in 2-h cycles in the presomitic mesoderm (PSM). PMID:15170214 instability of Hes7 is essential for sustained oscillation and for its function as a segmentation clock. |
| GO:0048511 rhythmic process | IMP PMID:15170214 Instability of Hes7 protein is crucial for the somite segmen... | ACCEPT | Summary: Hes7 mRNA and protein oscillate with a ~2-h period in the PSM (segmentation clock). Reason: Hes7 is itself a component of the oscillator (negative autoregulatory loop), so it directly participates in this rhythmic process. The term is broad; no specific segmentation-clock GO term exists. Supporting Evidence: PMID:11641270 Here, we found that Hes7 expression oscillates in 2-h cycles in the presomitic mesoderm (PSM). PMID:15170214 instability of Hes7 is essential for sustained oscillation and for its function as a segmentation clock. |
| GO:0050767 regulation of neurogenesis | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA (PANTHER:PTN000105428) regulation of neurogenesis, inherited from the neural Hes paralogs (Hes1, Hes5, Hes3). Reason: Mouse Hes7 expression is restricted to the presomitic mesoderm and its loss-of-function phenotype is confined to segmentation; there is no evidence for a neurogenesis role. The term is appropriate at the node for neural Hes genes but Hes7 appears to have diverged in expression domain. The zebrafish clock orthologue her1 receives the same IBA (same node) and is kept as non-core there because no her1-specific evidence of loss was found; for mouse Hes7 the PSM-restricted expression is explicit target-specific evidence of divergence, which is why the stronger demotion is used here. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: PANTHER:PTN000105428 SUPPORTS SOURCE BUT NOT TARGET Node spans neural Hes paralogs with neurogenesis evidence; Hes7 is PSM-restricted with no neural phenotype. Supporting Evidence: PMID:11260262 Strikingly, Hes7 is specifically expressed in the presomitic mesoderm in a dynamic manner. |
| GO:1990837 sequence-specific double-stranded DNA binding | IEA GO_REF:0000107 | ACCEPT | Summary: Orthology transfer (human HES7 Q9BYE0) of sequence-specific double-stranded DNA binding. Reason: Consistent with direct N-box binding shown for mouse Hes7 (PMID:16342160). |
| GO:1990837 sequence-specific double-stranded DNA binding | ISO GO_REF:0000119 | ACCEPT | Summary: Orthology transfer (human HES7 Q9BYE0) of sequence-specific double-stranded DNA binding. Reason: Consistent with direct N-box binding shown for mouse Hes7 (PMID:16342160). |
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Download this section (compressed HTML)Q: Does Hes7 act as a homodimer or as a heterodimer (e.g. with Hes1/Hey proteins) at the Lfng and Hes7 N-boxes in the PSM, and is Groucho/TLE recruitment through WRPW required for clock repression in vivo?
Experiment: Knock in a WRPW-deleted Hes7 allele and assay oscillation of Hes7/Lfng reporters in PSM explants to test whether Groucho/TLE recruitment is required for clock repression.
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