Go Annotations as Summary Text (Tabular View) (GO Graph)

GO curators for mouse genes have assigned the following annotations to the gene product of Hey2. (This text reflects annotations as of Thursday, July 24, 2014.)

---

Summary from NCBI RefSeq

[Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a member of the hairy and enhancer of split-related (HESR) family of basic helix-loop-helix (bHLH)-type transcription factors. The encoded protein forms homo- or hetero-dimers that localize to the nucleus and interact with a histone deacetylase complex to repress transcription. Expression of this gene is induced by the Notch signal transduction pathway. Two similar and redundant genes in mouse are required for embryonic cardiovascular development, and are also implicated in neurogenesis and somitogenesis. Alternatively spliced transcript variants have been found, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

---

Summary text based on GO annotations supported by experimental evidence in mouse

• Researchers have inferred from direct assay, that the gene product of Hey2
  • participates in the following biological processes:
    • cardiac muscle hypertrophy in response to stress ^[24]
    • negative regulation of Notch signaling pathway ^[21]
    • negative regulation of transcription from RNA polymerase II promoter ^{[1, 11]}
    • negative regulation of transcription from RNA polymerase II promoter involved in smooth muscle cell differentiation ^[21]
    • negative regulation of transcription regulatory region DNA binding ^[21]
    • negative regulation of transcription, DNA-templated ^[12]
    • Notch signaling pathway ^[19]
    • protein-DNA complex assembly ^{[1, 24]}
    • transcription from RNA polymerase II promoter ^[6]
  • performs the following molecular functions:
    • microsatellite binding ^[11]
    • RNA polymerase II core promoter sequence-specific DNA binding transcription factor activity ^[6]
    • sequence-specific DNA binding ^[8]
    • sequence-specific DNA binding transcription factor activity ^[12]
  • is located in the following cellular components:
    • cytoplasm ^[11]
    • nucleus ^{[11, 20]}
• The gene product of Hey2 has been shown to bind to the gene products of Heyl. ^{[6, 9, 10, 12]} Researchers have inferred, based on physical interactions, that the gene product of Hey2
  • performs the following molecular functions:
    • transcription factor binding ^[24]
• Researchers have inferred, based on phenotypic analysis of mouse mutants, that the gene product of Hey2
  • participates in the following biological processes:
    • ascending aorta morphogenesis ^[3]
    • atrial septum morphogenesis ^[3]
    • atrioventricular valve development ^[14]
    • cardiac epithelial to mesenchymal transition ^[4]
    • cardiac left ventricle morphogenesis ^[3]
    • cardiac muscle hypertrophy ^[18]
    • cardiac right ventricle morphogenesis ^[3]
    • cardiac septum morphogenesis ^[16]
    • cardiac vascular smooth muscle cell development ^[23]
    • cardiac ventricle morphogenesis ^[6]
    • cell fate commitment ^[2]
    • cochlea development ^[17]
    • coronary vasculature morphogenesis ^[23]
    • heart trabecula formation ^[16]
    • mesenchymal cell development ^[4]
    • muscular septum morphogenesis ^[3]
    • negative regulation of cardiac muscle cell apoptotic process ^[18]
    • negative regulation of gene expression ^{[7, 8, 18]}
    • negative regulation of Notch signaling pathway ^[20]
    • negative regulation of transcription from RNA polymerase II promoter ^{[7, 16]}
    • negative regulation of transcription, DNA-templated ^[6]
    • outflow tract morphogenesis ^[3]
    • pattern specification process ^[17]
    • positive regulation of cardiac muscle cell proliferation ^[13]
    • positive regulation of heart rate ^[14]
    • positive regulation of transcription from RNA polymerase II promoter ^{[4, 5]}
    • pulmonary artery morphogenesis ^[3]
    • pulmonary valve morphogenesis ^[3]
    • regulation of gene expression ^[23]
    • tricuspid valve formation ^[14]
    • tricuspid valve morphogenesis ^[3]
    • ventricular cardiac muscle cell development ^[13]
    • ventricular septum morphogenesis ^[3]
  • performs the following molecular functions:
    • DNA binding ^[20]
• Researchers have inferred, based on genetic interactions, that the gene product of Hey2
  • participates in the following biological processes:
    • anterior/posterior axis specification based on interactions with Hey1 ^[15]
    • arterial endothelial cell differentiation based on interactions with Hey1 ^[5]
    • artery development based on interactions with Hey1 ^[15]
    • blood vessel development based on interactions with Hey1 ^[15]
    • cochlea development based on interactions with Hes1, Hes5 ^[17]
    • dorsal aorta morphogenesis based on interactions with Hey1 ^[5]
    • endocardial cushion to mesenchymal transition involved in heart valve formation based on interactions with Hey1 ^[15]
    • labyrinthine layer blood vessel development based on interactions with Hey1 ^[5]
    • negative regulation of transcription from RNA polymerase II promoter based on interactions with Hes1, Id4, Runx2 ^[22]
    • pattern specification process based on interactions with Hes1, Hes5 ^[17]
    • regulation of auditory receptor cell differentiation based on interactions with Atoh1 ^[2]
    • regulation of vasculogenesis based on interactions with Hey1 ^[5]
    • umbilical cord morphogenesis based on interactions with Hey1 ^[5]
    • vasculogenesis based on interactions with Hey1 ^[5]
    • ventricular trabecula myocardium morphogenesis based on interactions with Hey1 ^[15]
• Based on the experimental annotations above, MGI curators have inferred, that the gene product of Hey2
  • participates in the following biological processes:
    • Notch signaling involved in heart development ^[3]

---

Summary text based on GO annotations supported by experimental evidence in other organisms

• From comparative sequence analysis (see table for details), MGI curators have determined that the gene product of Hey2:
  • participates in the following biological processes:
    • negative regulation of transcription from RNA polymerase II promoter
    • negative regulation of transcription initiation from RNA polymerase II promoter
    • negative regulation of transcription regulatory region DNA binding
    • negative regulation of transcription, DNA-templated
    • Notch signaling pathway
    • regulation of transcription from RNA polymerase II promoter
  • performs the following molecular functions:
    • histone deacetylase binding
    • microsatellite binding
    • protein binding transcription factor activity
    • RNA polymerase II activating transcription factor binding
    • sequence-specific DNA binding
    • sequence-specific DNA binding transcription factor activity
  • is located in the following cellular components:
    • nucleus
    • Sin3 complex
    • transcription factor complex
    • transcriptional repressor complex

---

Summary text based on GO annotations supported by structural data

• Hey2 encodes a protein or proteins that contain the following InterPro domains: Myc-type, basic helix-loop-helix (bHLH) domain, Orange, Orange subgroup, indicating that the gene product:
  • participates in the following biological processes:
    • regulation of transcription, DNA-templated
  • performs the following molecular functions:
    • protein dimerization activity

---

Summary text for additional MGI annotations

• Automated translation to GO terms of SwissProt keywords that describe Hey2 indicates that it:
  • participates in the following biological processes:
    • multicellular organismal development
    • regulation of transcription, DNA-templated
    • transcription, DNA-templated

---

References

1. Chin MT et al. (2000) Cardiovascular basic helix loop helix factor 1, a novel transcriptional repressor expressed preferentially in the developing and adult cardiovascular system. J Biol Chem, 275:6381-7. (PubMed:10692439)
2. Doetzlhofer A et al. (2009) Hey2 regulation by FGF provides a Notch-independent mechanism for maintaining pillar cell fate in the organ of Corti. Dev Cell, 16:58-69. (PubMed:19154718)
3. Donovan J et al. (2002) Tetralogy of fallot and other congenital heart defects in hey2 mutant mice. Curr Biol, 12:1605. (PubMed:12372254)
4. Fischer A et al. (2007) Combined loss of Hey1 and HeyL causes congenital heart defects because of impaired epithelial to mesenchymal transition. Circ Res, 100:856-63. (PubMed:17303760)
5. Fischer A et al. (2004) The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Genes Dev, 18:901-11. (PubMed:15107403)
6. Fischer A et al. (2005) Hey basic helix-loop-helix transcription factors are repressors of GATA4 and GATA6 and restrict expression of the GATA target gene ANF in fetal hearts. Mol Cell Biol, 25:8960-70. (PubMed:16199874)
7. Garg V et al. (2005) Mutations in NOTCH1 cause aortic valve disease. Nature, 437:270-4. (PubMed:16025100)
8. Heisig J et al. (2012) Target gene analysis by microarrays and chromatin immunoprecipitation identifies HEY proteins as highly redundant bHLH repressors. PLoS Genet, 8:e1002728. (PubMed:22615585)
9. Iso T et al. (2001) HERP, a novel heterodimer partner of HES/E(spl) in Notch signaling. Mol Cell Biol, 21:6080-9. (PubMed:11486045)
10. Jalali A et al. (2011) HeyL promotes neuronal differentiation of neural progenitor cells. J Neurosci Res, 89:299-309. (PubMed:21259317)
11. Kanno K et al. (2011) Differential effects of the HESR/HEY transcription factor family on dopamine transporter reporter gene expression via variable number of tandem repeats. J Neurosci Res, 89:562-75. (PubMed:21290414)
12. Kathiriya IS et al. (2004) Hairy-related transcription factors inhibit GATA-dependent cardiac gene expression through a signal-responsive mechanism. J Biol Chem, 279:54937-43. (PubMed:15485867)
13. Koibuchi N et al. (2007) CHF1/Hey2 plays a pivotal role in left ventricular maturation through suppression of ectopic atrial gene expression. Circ Res, 100:850-5. (PubMed:17332425)
14. Kokubo H et al. (2004) Targeted disruption of hesr2 results in atrioventricular valve anomalies that lead to heart dysfunction. Circ Res, 95:540-7. (PubMed:15297376)
15. Kokubo H et al. (2005) Mouse hesr1 and hesr2 genes are redundantly required to mediate Notch signaling in the developing cardiovascular system. Dev Biol, 278:301-9. (PubMed:15680351)
16. Kokubo H et al. (2007) Hesr1 and Hesr2 regulate atrioventricular boundary formation in the developing heart through the repression of Tbx2. Development, 134:747-55. (PubMed:17259303)
17. Li S et al. (2008) Hey2 functions in parallel with Hes1 and Hes5 for mammalian auditory sensory organ development. BMC Dev Biol, 8:20. (PubMed:18302773)
18. Liu Y et al. (2010) The bHLH transcription factor CHF1/Hey2 regulates susceptibility to apoptosis and heart failure after pressure overload. Am J Physiol Heart Circ Physiol, 298:H2082-92. (PubMed:20382855)
19. Maier MM et al. (2000) Comparative analysis of the human and mouse Hey1 promoter: Hey genes are new Notch target genes. Biochem Biophys Res Commun, 275:652-60. (PubMed:10964718)
20. Nakagawa O et al. (2000) Members of the HRT family of basic helix-loop-helix proteins act as transcriptional repressors downstream of Notch signaling. Proc Natl Acad Sci U S A, 97:13655-60. (PubMed:11095750)
21. Tang Y et al. (2008) Hairy-related transcription factors inhibit Notch-induced smooth muscle alpha-actin expression by interfering with Notch intracellular domain/CBF-1 complex interaction with the CBF-1-binding site. Circ Res, 102:661-8. (PubMed:18239137)
22. Tokuzawa Y et al. (2010) Id4, a new candidate gene for senile osteoporosis, acts as a molecular switch promoting osteoblast differentiation. PLoS Genet, 6:e1001019. (PubMed:20628571)
23. Watanabe T et al. (2010) Transcription factor CHF1/Hey2 regulates coronary vascular maturation. Mech Dev, 127:418-27. (PubMed:20619341)
24. Xiang F et al. (2006) Transcription factor CHF1/Hey2 suppresses cardiac hypertrophy through an inhibitory interaction with GATA4. Am J Physiol Heart Circ Physiol, 290:H1997-2006. (PubMed:16603706)

---

---

Gene Ontology Evidence Code Abbreviations:

EXP Inferred from experiment

IC Inferred by curator

IDA Inferred from direct assay

IEA Inferred from electronic annotation

IGI Inferred from genetic interaction

IMP Inferred from mutant phenotype

IPI Inferred from physical interaction

ISS Inferred from sequence or structural similarity

ISO Inferred from sequence orthology

ISA Inferred from sequence alignment

ISM Inferred from sequence model

NAS Non-traceable author statement

ND No biological data available

RCA Reviewed computational analysis

TAS Traceable author statement

---