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

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

Research output: Contribution to journalArticle

20 Citations (Scopus)

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 Develomental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.

Original languageEnglish (US)
JournalBiochimica et Biophysica Acta - Molecular Cell Research
DOIs
StateAccepted/In press - Jan 6 2016

Fingerprint

Epigenomics
Chromatin
Chromatin Assembly and Disassembly
Nucleosomes
Cardiac Myocytes
Methylation
Histone Code
Ventricular Function
Methyltransferases
DNA Methylation
Cardiomyopathies
Cues
DNA
Genes
Therapeutics

Keywords

  • Brg1
  • Cardiac hypertrophy
  • Cardiomyopathy
  • Chromatin remodeling
  • DNA methylation
  • Dnmt
  • G9a
  • Gene silencing
  • H3K9me2
  • Heart failure
  • Histone methylation
  • Myosin heavy chain

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Epigenetic response to environmental stress : Assembly of BRG1-G9a/GLP-DNMT3 repressive chromatin complex on Myh6 promoter in pathologically stressed hearts. / Han, Pei; Li, Wei; Yang, Jin; Shang, Ching; Lin, Chiou Hong; Cheng, Wei; Hang, Calvin T.; Cheng, Hsiu Ling; Chen, Chen Hao; Wong, Johnson; Xiong, Yiqin; Zhao, Mingming; Drakos, Stavros G.; Ghetti, Andrea; Li, Dean Y.; Bernstein, Daniel; Chen, Huei sheng Vincent; Quertermous, Thomas; Chang, Ching-Pin.

In: Biochimica et Biophysica Acta - Molecular Cell Research, 06.01.2016.

Research output: Contribution to journalArticle

Han, P, Li, W, Yang, J, Shang, C, Lin, CH, Cheng, W, Hang, CT, Cheng, HL, Chen, CH, Wong, J, Xiong, Y, Zhao, M, Drakos, SG, Ghetti, A, Li, DY, Bernstein, D, Chen, HSV, Quertermous, T & Chang, C-P 2016, 'Epigenetic response to environmental stress: Assembly of BRG1-G9a/GLP-DNMT3 repressive chromatin complex on Myh6 promoter in pathologically stressed hearts', Biochimica et Biophysica Acta - Molecular Cell Research. https://doi.org/10.1016/j.bbamcr.2016.03.002
Han, Pei ; Li, Wei ; Yang, Jin ; Shang, Ching ; Lin, Chiou Hong ; Cheng, Wei ; Hang, Calvin T. ; Cheng, Hsiu Ling ; Chen, Chen Hao ; Wong, Johnson ; Xiong, Yiqin ; Zhao, Mingming ; Drakos, Stavros G. ; Ghetti, Andrea ; Li, Dean Y. ; Bernstein, Daniel ; Chen, Huei sheng Vincent ; Quertermous, Thomas ; Chang, Ching-Pin. / Epigenetic response to environmental stress : Assembly of BRG1-G9a/GLP-DNMT3 repressive chromatin complex on Myh6 promoter in pathologically stressed hearts. In: Biochimica et Biophysica Acta - Molecular Cell Research. 2016.
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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 Develomental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.",
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AU - Yang, Jin

AU - Shang, Ching

AU - Lin, Chiou Hong

AU - Cheng, Wei

AU - Hang, Calvin T.

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AU - Zhao, Mingming

AU - Drakos, Stavros G.

AU - Ghetti, Andrea

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