title: Epigenetic response to environmental stress: Assembly of BRG1-G9a/GLP-DNMT3 repressive chromatin complex on Myh6 promoter in pathologically stressed hearts.
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.
authors.affiliation: Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Pei
authors.initials: P
authors.lastname: Han
authors.affiliation: Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Yang
authors.affiliation: Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Ching
authors.initials: C
authors.lastname: Shang
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Chiou-Hong
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Cheng
authors.affiliation: Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Calvin T
authors.initials: CT
authors.lastname: Hang
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Hsiu-Ling
authors.initials: HL
authors.lastname: Cheng
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Chen-Hao
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Del E. Webb Neuroscience, Aging & Stem Cell Research Center, Sanford/Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Johnson
authors.initials: J
authors.lastname: Wong
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Yiqin
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Division of Cardiovascular Medicine, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Cardiovascular Department and Utah Artificial Heart Program, Intermountain Medical Center, Salt Lake City, UT 84112, USA.
authors.forename: Stavros G
authors.initials: SG
authors.lastname: Drakos
authors.affiliation: AnaBios Corporation, 3030 Bunker Hill St., San Diego, CA 92109, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ghetti
authors.affiliation: Cardiovascular Department and Utah Artificial Heart Program, Intermountain Medical Center, Salt Lake City, UT 84112, USA.
authors.forename: Dean Y
authors.initials: DY
authors.lastname: Li
authors.affiliation: Division of Cardiovascular Medicine, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bernstein
authors.affiliation: Del E. Webb Neuroscience, Aging & Stem Cell Research Center, Sanford/Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Huei-Sheng Vincent
authors.initials: HS
authors.lastname: Chen
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
authors.affiliation: Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Krannert Institute of Cardiology and Division of Cardiology, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Krannert Institute of Cardiology and Division of Cardiology, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: changcp@iu.edu.
authors.forename: Ching-Pin
authors.initials: CP
authors.lastname: Chang
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009202:Cardiomyopathies / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D018899:CpG Islands; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004265:DNA Helicases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D005865:Gestational Age; D011495:Histone-Lysine N-Methyltransferase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D020127:Recovery of Function; D015398:Signal Transduction; D013312:Stress, Physiological; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016277:Ventricular Function, Left
chemical_list: D002843:Chromatin; C000717967:DNMT3A protein, human; D006657:Histones; C584019:Myh6 protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C533711:G9a protein, mouse; C513479:GLP protein, mouse; D011495:Histone-Lysine N-Methyltransferase; C513194:Smarca4 protein, mouse; D004265:DNA Helicases; D018995:Myosin Heavy Chains
keywords: Brg1; Cardiac hypertrophy; Cardiomyopathy; Chromatin remodeling; DNA methylation; Dnmt; G9a; Gene silencing; H3K9me2; Heart failure; Histone methylation; Myosin heavy chain