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HEY2  -  hes-related family bHLH transcription...

Homo sapiens

Synonyms: BHLHB32, CHF1, Cardiovascular helix-loop-helix factor 1, Class B basic helix-loop-helix protein 32, GRIDLOCK, ...
 
 
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Disease relevance of HEY2

  • Although the high incidence and variability of human congenital heart defects implies a multifactorial genetic basis, our results suggest that mutation of HEY2 is not a major contributing factor [1].
  • ZFPM2/FOG2 and HEY2 genes analysis in nonsyndromic tricuspid atresia [2].
  • We and others have recently shown that in mice loss of Hey2 results in a high incidence of fatal ventricular and atrial septal defects, combined with tricuspid stenosis or atresia in some cases [1].
  • Therefore, we studied the mechanism of Herp CpG islands regulation by luciferase assays and mRNA analysis in neuronal SH-SY5Y (human neuroblastoma cell line) and HEK 293T (human embryonic kidney 293T) cells [3].
  • Body weight (BW), body composition, leptin concentration, attitude toward eating (measured with the Three-Factor Eating Questionnaire), physical activity, and the polymorphisms of the PPARgamma2, GRL, and CNTF genes were measured [4].
 

High impact information on HEY2

 

Biological context of HEY2

 

Anatomical context of HEY2

  • Endothelial progenitor cells (EPCs) contain high amounts of COUP-TFII, a regulator of vein identity, while levels of the arterial regulators Dll4 and Hey2 are low [11].
  • Forced expression of Notch intracellular domain (NICD, activated form of Notch) induced mRNA expression for a subset of arterial-specific markers such as ephrinB2, connexin40, and HERP1 only in EC but not other cell lines [12].
  • Our findings highlight an important transcriptional mechanism by which CHF1/Hey2 may affect smooth-muscle cell phenotype [13].
  • In Hey2-deficient fetal hearts we observed elevated mRNA levels of ANF and CARP [14].
  • Hey2 is similarly expressed in the somites whereas it shows a complementary expression in the heart, the craniofacial region and the nervous system [15].
 

Associations of HEY2 with chemical compounds

  • Expression of ANF and Hey2 is normally restricted to the trabecular and compact myocardial layer, respectively [14].
  • Expression of Herp protein is up-regulated in response to ER stress, including homocysteine [3].
  • Herp stabilizes neuronal Ca(2+) homeostasis and is involved in improving the balance of the folding capacity and protein loading in the ER [3].
  • Stimulation with SAM (S-adenosyl methionine) and homocysteine led to an increase in Herp promoter methylation, which correlated to an acute decrease in luciferase expression in SAM, but not in homocysteine stimulated cells [3].
  • In the early period of ER stress (0-8 h after tunicamycin treatment), Herp null cells displayed enhanced ER stress signalling and stabilization of an endogenous ERAD substrate, compared with wild-type cells [16].
 

Physical interactions of HEY2

 

Regulatory relationships of HEY2

 

Other interactions of HEY2

  • HERP, a new primary target of Notch regulated by ligand binding [18].
  • Rather, HERP uses its bHLH domain to recruit the mSin3 complex containing histone deacetylase HDAC1 and an additional corepressor, N-CoR, to mediate repression [9].
  • Expression of both HERP1 and myocardin was elevated in cultured VSMCs compared with medial SMC [17].
  • HERP1 protein interfered with the SRF/CArG-box interaction in vivo and in vitro [17].
  • Therefore, we screened 40 individuals affected by nonsyndromic TriAt for ZFPM2/FOG2 and HEY2 gene mutations [2].
 

Analytical, diagnostic and therapeutic context of HEY2

  • Mutagenesis studies and chromatin immunoprecipitation assays showed that Luman physically associates with the Herp promoter, specifically the second half-site (CCACG) of ERSE-II [7].
  • The more successful genotypes showed a higher baseline body mass index and waist circumference (PPARgamma2), a greater decrease in disinhibition of dietary restraint (GRL), and less sensation of hunger (GRL) [4].
  • METHODS: The HERP mRNA expression level was measured by quantitative PCR in the blood of 66 male alcoholic patients and 55 nondrinking healthy controls [19].
  • GRL Bcl I, alpha 2A-ADR Dra I and beta 2-ADR Ban I markers were typed by Southern blot, and other markers by polymerase chain reaction technique [20].
  • However, animal models have suggested a role of cardiogenic Zfpm2/Fog2 and Hey2 genes in the pathogenesis of TriAt [2].

References

  1. Phenotypic variability in Hey2 -/- mice and absence of HEY2 mutations in patients with congenital heart defects or Alagille syndrome. Fischer, A., Klamt, B., Schumacher, N., Glaeser, C., Hansmann, I., Fenge, H., Gessler, M. Mamm. Genome (2004) [Pubmed]
  2. ZFPM2/FOG2 and HEY2 genes analysis in nonsyndromic tricuspid atresia. Sarkozy, A., Conti, E., D'Agostino, R., Digilio, M.C., Formigari, R., Picchio, F., Marino, B., Pizzuti, A., Dallapiccola, B. Am. J. Med. Genet. A (2005) [Pubmed]
  3. Homocysteine regulates expression of Herp by DNA methylation involving the AARE and CREB binding sites. Lenz, B., Bleich, S., Beutler, S., Schlierf, B., Schwager, K., Reulbach, U., Kornhuber, J., B??nsch, D. Exp. Cell Res. (2006) [Pubmed]
  4. Relation of weight maintenance and dietary restraint to peroxisome proliferator-activated receptor gamma2, glucocorticoid receptor, and ciliary neurotrophic factor polymorphisms. Vogels, N., Mariman, E.C., Bouwman, F.G., Kester, A.D., Diepvens, K., Westerterp-Plantenga, M.S. Am. J. Clin. Nutr. (2005) [Pubmed]
  5. The gene for an inherited form of deafness maps to chromosome 5q31. Leon, P.E., Raventos, H., Lynch, E., Morrow, J., King, M.C. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  6. Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function. Williams, C.K., Li, J.L., Murga, M., Harris, A.L., Tosato, G. Blood (2006) [Pubmed]
  7. Luman/CREB3 Induces Transcription of the Endoplasmic Reticulum (ER) Stress Response Protein Herp through an ER Stress Response Element. Liang, G., Audas, T.E., Li, Y., Cockram, G.P., Dean, J.D., Martyn, A.C., Kokame, K., Lu, R. Mol. Cell. Biol. (2006) [Pubmed]
  8. Characterization of the human and mouse HEY1, HEY2, and HEYL genes: cloning, mapping, and mutation screening of a new bHLH gene family. Steidl, C., Leimeister, C., Klamt, B., Maier, M., Nanda, I., Dixon, M., Clarke, R., Schmid, M., Gessler, M. Genomics (2000) [Pubmed]
  9. HERP, a novel heterodimer partner of HES/E(spl) in Notch signaling. Iso, T., Sartorelli, V., Poizat, C., Iezzi, S., Wu, H.Y., Chung, G., Kedes, L., Hamamori, Y. Mol. Cell. Biol. (2001) [Pubmed]
  10. Developmental patterning of the cardiac atrioventricular canal by Notch and Hairy-related transcription factors. Rutenberg, J.B., Fischer, A., Jia, H., Gessler, M., Zhong, T.P., Mercola, M. Development (2006) [Pubmed]
  11. Hypoxia-mediated activation of Dll4-Notch-Hey2 signaling in endothelial progenitor cells and adoption of arterial cell fate. Diez, H., Fischer, A., Winkler, A., Hu, C.J., Hatzopoulos, A.K., Breier, G., Gessler, M. Exp. Cell Res. (2007) [Pubmed]
  12. Dll4-selective Notch signaling induces ephrinB2 gene expression in endothelial cells. Iso, T., Maeno, T., Oike, Y., Yamazaki, M., Doi, H., Arai, M., Kurabayashi, M. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  13. CHF1/Hey2 suppresses SM-MHC promoter activity through an interaction with GATA-6. Shirvani, S., Xiang, F., Koibuchi, N., Chin, M.T. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  14. 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. Fischer, A., Klattig, J., Kneitz, B., Diez, H., Maier, M., Holtmann, B., Englert, C., Gessler, M. Mol. Cell. Biol. (2005) [Pubmed]
  15. Hey genes: a novel subfamily of hairy- and Enhancer of split related genes specifically expressed during mouse embryogenesis. Leimeister, C., Externbrink, A., Klamt, B., Gessler, M. Mech. Dev. (1999) [Pubmed]
  16. Role of Herp in the endoplasmic reticulum stress response. Hori, O., Ichinoda, F., Yamaguchi, A., Tamatani, T., Taniguchi, M., Koyama, Y., Katayama, T., Tohyama, M., Stern, D.M., Ozawa, K., Kitao, Y., Ogawa, S. Genes Cells (2004) [Pubmed]
  17. HERP1 inhibits myocardin-induced vascular smooth muscle cell differentiation by interfering with SRF binding to CArG box. Doi, H., Iso, T., Yamazaki, M., Akiyama, H., Kanai, H., Sato, H., Kawai-Kowase, K., Tanaka, T., Maeno, T., Okamoto, E., Arai, M., Kedes, L., Kurabayashi, M. Arterioscler. Thromb. Vasc. Biol. (2005) [Pubmed]
  18. HERP, a new primary target of Notch regulated by ligand binding. Iso, T., Sartorelli, V., Chung, G., Shichinohe, T., Kedes, L., Hamamori, Y. Mol. Cell. Biol. (2001) [Pubmed]
  19. Epigenetic DNA hypermethylation of the HERP gene promoter induces down-regulation of its mRNA expression in patients with alcohol dependence. Bleich, S., Lenz, B., Ziegenbein, M., Beutler, S., Frieling, H., Kornhuber, J., Bönsch, D. Alcohol. Clin. Exp. Res. (2006) [Pubmed]
  20. Interactions among the glucocorticoid receptor, lipoprotein lipase and adrenergic receptor genes and abdominal fat in the Québec Family Study. Ukkola, O., Pérusse, L., Chagnon, Y.C., Després, J.P., Bouchard, C. Int. J. Obes. Relat. Metab. Disord. (2001) [Pubmed]
 
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