Disease relevance of HEY1

• KSHV RTA induces a transcriptional repressor, HEY1 that represses rta promoter [1].
• Expression of the HESR1 gene in retinal vascular endothelial cells may protect retinal blood vessels and may be useful in the treatment of diseases involving damage to the retinal vasculature, including diabetic retinopathy, age-related macular degeneration, and retinal vein occlusion [2].
• To examine the role of HESR1 in retinal neovascularization, we transfected retinal vascular endothelial cells (HRCECs) with the HESR1 gene and studied its effects on the expression of angiogenic factors, on the proliferation and migration of endothelial cells, and on the formation of tube-like structures (TLSs) [2].
• Combined loss of Hey1 and HeyL causes congenital heart defects because of impaired epithelial to mesenchymal transition [3].
• Hey1 colocalizes with AR in the epithelia of patients with benign prostatic hyperplasia, where it is found in both the cytoplasm and the nucleus [4].

Psychiatry related information on HEY1

• Moreover, young adults of Hesr1 knockout mice showed a decrease in spontaneous locomotor activity and a reduction in exploratory behavior or behavioral responses to novelty in the open-field, and elevated plus-maze tests [5].

High impact information on HEY1

• This strain was used to generate paired Hey2- and Hey1/2-deficient embryonic stem cell lines [6].
• In marked contrast, we demonstrate that Hey1 is excluded from the nucleus in most human prostate cancers, raising the possibility that an abnormal Hey1 subcellular distribution may have a role in the aberrant hormonal responses observed in prostate cancer [4].
• Jun blockade of erythropoiesis: role for repression of GATA-1 by HERP2 [7].
• Furthermore, transduction of HERP2 into primary human hematopoietic progenitors inhibited erythroid differentiation [7].
• HERP2 showed physical interaction with GATA-1 and repressed GATA-1 transcriptional activation [7].

Biological context of HEY1

• The genes were mapped by fluorescence in situ hybridization and RH mapping to the following human chromosomes: (HEY1) 8q21, (HEY2) 6q21, and (HEYL) 1p34 [8].
• Down-regulation of DLL4 expression with RNA interference led to decreased expression of HEY1 and EphrinB2, and the inhibition of endothelial cell proliferation, migration, and network formation, all of which are important processes in tumor angiogenesis [9].
• Electrophoretic mobility shift analysis indicated that CHF2 inhibits the binding of the MyoD.E47 heterodimer to the E-box binding site [10].
• Our data indicate that CHF2 functions as a transcriptional repressor of myogenesis by formation of an inactive heterodimeric complex with MyoD and likely plays an important role in muscle development [10].
• Activation of Notch1 and Notch4 induced the VSMC-selective target genes HRT1 and HRT2, promoted cell cycle transit in smooth muscle cells, and led to loss of density-dependent growth inhibition [11].

Anatomical context of HEY1

• In a luciferase reporter system, RTA activated the hey1 promoter in several cell lines; conversely, HEY1 repressed the rta promoter [1].
• After induction of myotube formation in low serum, CHF2 expression is barely detectable at 3 days after induction [10].
• In undifferentiated myoblasts, CHF2 is expressed at high levels [10].
• Analysis of embryonic murine hesr-1 expression by in situ hybridization reveals strong expression in the somitic mesoderm, the central nervous system, the kidney, the heart, nasal epithelium, and limbs indicating a role for hesr-1 in the development of these tissues [12].
• HESR1 is necessary for the induction of a tubular network and for continued maintenance of mature and quiescent blood vessels [2].

Associations of HEY1 with chemical compounds

• While the overall structure with the bHLH domain, Orange domain, and WRPW motif is similar, the last motif is changed to KPYRPWG in Hey1/2 and absent in HeyL [8].
• These results suggest that Hesr1 and its polymorphism(s) might be involved in dopamine-related polygenic disorders and behavioral traits [13].
• METHODS: A total of 321 postmenopausal women were randomized to 1 mg 17beta-estradiol plus 0.025 mg gestodene for 12 days every month (HRT 1), or 1 mg 17beta-estradiol plus 0.025 mg gestodene for 12 days every third month (HRT 2), or no-HRT, during 48 weeks [14].
• In general, the sulfonamide analogues with a CHF2 at C-3 were found to be more potent than those having a CF3 group [15].
• Among the subjects with the usual phenotype, the CHF2 C5- phenotype was more frequent in the mildly poisoned group (94.3%) than in the control group (81.0%), leading to an RR of 3.9 when compared to the CHE2 C5+ phenotype [16].

Regulatory relationships of HEY1

• Thus, HESR1 represses VEGFR2 through interactions with SP-1-like factors and requires an Inr element in the absence of a TATA box [17].
• HESR1 seems to inhibit the vessel-promoting effects of VEGF, shift endothelial cells from a proliferative state to a quiescent state, and restore normal vessel structures [2].

Other interactions of HEY1

• We have isolated and characterized three new hairy-related bHLH transcription factor genes from mouse and human (hairy and Enhancer-of-split related with YRPW motif; HEY1, HEY2, and HEYL) [8].
• Importantly, HERP2 is an immediate target gene of Notch signaling since HERP2 mRNA expression is induced even in the absence of de novo protein synthesis [18].
• The VEGFR2 promoter contains a functional initiator element but no TATA box, however, addition of a TATA sequence renders the promoter resistant to inhibition by HESR1 [17].
• Which co-repressors are required in vivo for AR repression by anti-androgens is not clear, but one candidate is the Notch effector Hey1 [19].

Analytical, diagnostic and therapeutic context of HEY1

• We assessed the risk of breast cancer associated with HRT use in 54,548 postmenopausal women who had never taken any HRT 1 year before entering the E3N-EPIC cohort study (mean age at inclusion: 52.8 years); 948 primary invasive breast cancers were diagnosed during follow-up (mean duration: 5.8 years) [20].
• To investigate functions of the HESR1 gene in the dopaminergic nervous system in vivo, we analyzed the expressions of dopamine-related genes in the postnatal day 0 whole brains of Hesr1 knockout mice by real-time RT-PCR analysis [5].
• Using DNA chip technology, we showed that hey1, a basic helix-loop-helix-containing transcription factor, increased three- to fourfold in this line [1].
• Two distinct PCR fragments, chf1 and chf2, were isolated and used to identify two DNA contigs [21].

References