Epigenetic response to environmental stress: Assembly of BRG1-G9a/GLP-DNMT3 repressive chromatin complex on Myh6 promoter in pathologically stressed hearts

被引：50

作者：

Han, Pei ^{[1
,2
,5
]}

Li, Wei ^{[1
,2
,5
]}

Yang, Jin ^{[1
,2
]}

Shang, Ching ^{[1
,2
,5
]}

Lin, Chiou-Hong ^{[5
]}

Cheng, Wei ^{[1
,2
]}

Hang, Calvin T. ^{[1
,2
,5
]}

Cheng, Hsiu-Ling ^{[5
]}

Chen, Chen-Hao ^{[5
]}

Wong, Johnson ^{[10
]}

Xiong, Yiqin ^{[5
]}

Zhao, Mingming ^{[6
]}

Drakos, Stavros G. ^{[7
,8
]}

Ghetti, Andrea ^{[9
]}

Li, Dean Y. ^{[7
,8
]}

Bernstein, Daniel ^{[6
]}

Chen, Huei-sheng Vincent ^{[10
]}

Quertermous, Thomas ^{[5
]}

Chang, Ching-Pin ^{[1
,2
,3
,4
]}

机构：

[1] Indiana Univ Sch Med, Krannert Inst Cardiol, Indianapolis, IN 46202 USA

[2] Indiana Univ Sch Med, Div Cardiol, Dept Med, Indianapolis, IN 46202 USA

[3] Indiana Univ Sch Med, Div Cardiol, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA

[4] Indiana Univ Sch Med, Div Cardiol, Dept Med & Mol Genet, Indianapolis, IN 46202 USA

[5] Stanford Univ, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA

[6] Stanford Univ, Div Cardiovasc Med, Dept Pediat, Stanford, CA 94305 USA

[7] Intermt Med Ctr, Cardiovasc Dept, Salt Lake City, UT 84112 USA

[8] Intermt Med Ctr, Utah Artificial Heart Program, Salt Lake City, UT 84112 USA

[9] AnaBios Corp, 3030 Bunker Hill St, San Diego, CA 92109 USA

[10] Sanford Burnham Med Res Inst, Del E Webb Neurosci, Aging & Stem Cell Res Ctr, La Jolla, CA 92037 USA

来源：

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH | 2016年 / 1863卷 / 07期

关键词：

Histone methylation; DNA methylation; Chromatin remodeling; Gene silencing; Myosin heavy chain; G9a; Dnmt; Brg1; H3K9me2; Cardiac hypertrophy; Cardiomyopathy; Heart failure; MYOSIN HEAVY-CHAIN; DNA METHYLATION; CONTRACTILE KINETICS; ISOFORM EXPRESSION; GENE-EXPRESSION; METHYLTRANSFERASES; MYOCARDIUM; MUSCLE; INHIBITION; DISEASE;

D O I：

10.1016/j.bbamcr.2016.03.002

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Chromatin structure is determined by nucleosome positioning, histone modifications, and DNA methylation. How chromatin modifications are coordinately altered under pathological conditions remains elusive. Here we describe a stress-activated mechanism of concerted chromatin modification in the heart. In mice, pathological stress activates cardiomyocytes to express Brg1 (nucleosome-remodeling factor), G9a/Glp (histone methyltransferase), and Dnmt3 (DNA methyltransferase). Once activated, Brg1 recruits G9a and then Dnmt3 to sequentially assemble repressive chromatin marked by H3K9 and CpG methylation on a key molecular motor gene (Myh6), thereby silencing Myh6 and impairing cardiac contraction. Disruption of Brg1, G9a or Dnmt3 erases repressive chromatin marks and de-represses Myh6, reducing stress-induced cardiac dysfunction. In human hypertrophic hearts, BRG1-G9a/GLP-DNMT3 complex is also activated; its level correlates with H3K9/CpG methylation, Myh6 repression, and cardiomyopathy. Our studies demonstrate a new mechanism of chromatin assembly in stressed hearts and novel therapeutic targets for restoring Myh6 and ventricular function. The stress-induced Brg1-G9a-Dnmt3 interactions and sequence of repressive chromatin assembly on Myh6 illustrates a molecular mechanism by which the heart epigenetically responds to environmental signals. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel. (c) 2016 Published by Elsevier B.V.

引用

页码：1772 / 1781

页数：10

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