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

Biochim Biophys Acta. 2016 Jul;1863(7 Pt B):1772-81. doi: 10.1016/j.bbamcr.2016.03.002. Epub 2016 Mar 4.

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.

Keywords: Brg1; Cardiac hypertrophy; Cardiomyopathy; Chromatin remodeling; DNA methylation; Dnmt; G9a; Gene silencing; H3K9me2; Heart failure; Histone methylation; Myosin heavy chain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological
  • Animals
  • Cardiomegaly / enzymology*
  • Cardiomegaly / genetics
  • Cardiomegaly / pathology
  • Cardiomegaly / physiopathology
  • Cardiomyopathies / enzymology*
  • Cardiomyopathies / genetics
  • Cardiomyopathies / pathology
  • Cardiomyopathies / physiopathology
  • Chromatin / genetics
  • Chromatin / metabolism*
  • Chromatin Assembly and Disassembly*
  • CpG Islands
  • DNA (Cytosine-5-)-Methyltransferases / deficiency
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism*
  • DNA Helicases / deficiency
  • DNA Helicases / genetics
  • DNA Helicases / metabolism*
  • DNA Methylation
  • DNA Methyltransferase 3A
  • Disease Models, Animal
  • Epigenesis, Genetic*
  • Gestational Age
  • Histone-Lysine N-Methyltransferase / deficiency
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Histones / metabolism
  • Humans
  • Methylation
  • Mice, Knockout
  • Myocardium / enzymology*
  • Myocardium / pathology
  • Myosin Heavy Chains / genetics
  • Myosin Heavy Chains / metabolism*
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Promoter Regions, Genetic*
  • Protein Binding
  • Protein Processing, Post-Translational
  • Recovery of Function
  • Signal Transduction
  • Stress, Physiological*
  • Transcription Factors / deficiency
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Ventricular Function, Left

Substances

  • Chromatin
  • DNMT3A protein, human
  • Histones
  • Myh6 protein, mouse
  • Nuclear Proteins
  • Transcription Factors
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA Methyltransferase 3A
  • G9a protein, mouse
  • GLP protein, mouse
  • Histone-Lysine N-Methyltransferase
  • Smarca4 protein, mouse
  • DNA Helicases
  • Myosin Heavy Chains