Epigenetic Response to Environmental Stress: Assembly of BRG1-G9a/GLP-DNMT3 Repressive Chromatin Complex on Myh6 Promoter in Pathologically Stressed Hearts

Overview

Journal Biochim Biophys Acta

Specialties Biochemistry
Biophysics

Date 2016 Mar 9

PMID 26952936

Citations 38

Authors

Pei Han

Wei Li

Jin Yang

Ching Shang

Chiou-Hong Lin

Wei Cheng

Calvin T Hang

Hsiu-Ling Cheng

Chen-Hao Chen

Johnson Wong

Yiqin Xiong

Mingming Zhao

Stavros G Drakos

Andrea Ghetti

Dean Y Li

Daniel Bernstein

Huei-Sheng Vincent Chen

Thomas Quertermous

Ching-Pin Chang

Affiliations

Soon will be listed here.

Abstract

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.

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