Mechanisms of epigenetic and cell-type specific regulation of Hey target genes in ES cells and cardiomyocytes |
| |
| Affiliation: | 1. Developmental Biochemistry, Theodor Boveri Institute (Biocenter), University of Wuerzburg, Am Hubland, D-97074 Wuerzburg, Germany;2. Physiological Chemistry, Theodor Boveri Institute (Biocenter), University of Wuerzburg, Am Hubland, D-97074 Wuerzburg, Germany;3. Biochemistry and Molecular Biology, Theodor Boveri Institute (Biocenter), University of Wuerzburg, Am Hubland, D-97074 Wuerzburg, Germany;4. Comprehensive Cancer Center Mainfranken, University of Wuerzburg, Am Hubland, D-97074 Wuerzburg, Germany;5. Comprehensive Heart Failure Center, University of Wuerzburg, Am Hubland, D-97074 Wuerzburg, Germany;1. Department of Cardiology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China;2. Department of Cardiology, Wenzhou People''s Hospital, Wenzhou, Zhejiang, China;3. Department of Orthopedics, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China;4. Institute of Translational Medicine, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China;1. Department of Physics, Government College of Engineering and Textile Technology, 12 William Carey Road, Serampore, Hooghly 712201, India;2. Centre for Nano and Soft Matter Sciences, Jalahalli, Bangalore 560013, India;1. Department of Chemistry, J.K.C.C., Acharya Nagarjuna University, Guntur 522510, AP, India;2. Department of Physics, Raylaseema University, Kurnool, Andhra Pradesh, India;3. Department of Chemistry, Acharya Nagarjuna University, Guntur 522510, AP, India;1. Faculty of Agriculture and Life Science, Hirosaki University, Hirosaki, Aomori 036-8561, Japan;2. Faculty of Chemistry, Materials and Bioengineering, Kansai University, Suita, Osaka 564-8680, Japan;1. Department of Biochemistry and Cancer Biology, University of Toledo College of Medicine, Toledo, OH, USA;2. Marshall Institute for Interdisciplinary Research, Huntington, WV, USA;3. Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine and Harrington Heart & Vascular Institute, University Hospitals Case Medical Center, Cleveland, OH, USA |
| |
| Abstract: | Hey bHLH transcription factors are critical effectors of Notch signaling. During mammalian heart development they are expressed in atrial and ventricular cardiomyocytes and in the developing endocardium. Hey knockout mice suffer from lethal cardiac defects, such as ventricular septum defects, valve defects and cardiomyopathy. Despite this functional relevance, little is known about the regulation of downstream targets in relevant cell types. The objective of this study was to elucidate the regulatory mechanisms by which Hey proteins affect gene expression in a cell type specific manner.We used an in vitro cardiomyocyte differentiation system with inducible Hey1 or Hey2 expression to study target gene regulation in cardiomyocytes (CM) generated from murine embryonic stem cells (ESC). The effects of Hey1 and Hey2 are largely redundant, but cell type specific. The number of regulated genes is comparable between ESC and CM, but the total number of binding sites is much higher, especially in ESC, targeting mainly genes involved in transcriptional regulation and developmental processes. Repression by Hey proteins generally correlates with the extent of Hey-binding to target promoters, Hdac recruitment and lower histone acetylation. Functionally, treatment with the Hdac inhibitor TSA abolished Hey target gene regulation. However, in CM the repressive effect of Hey-binding is lost for a subset of genes. These also lack Hey-dependent histone deacetylation in CM and are enriched for binding sites of cardiac specific activators like Srf, Nkx2-5, and Gata4. Ectopic Nkx2-5 overexpression in ESC blocks Hey-mediated repression of these genes.Thus, Hey proteins mechanistically repress target genes via Hdac recruitment and histone deacetylation. In CM Hey-repression is counteracted by cardiac activators, which recruit histone acetylases and prevent Hey mediated deacetylation and subsequent repression for a subset of genes. |
| |
| Keywords: | |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
