title: BRG1 and BRM function antagonistically with c-MYC in adult cardiomyocytes to regulate conduction and contractility.
abstract: The contractile dysfunction that underlies heart failure involves perturbations in multiple biological processes ranging from metabolism to electrophysiology. Yet the epigenetic mechanisms that are altered in this disease state have not been elucidated. SWI/SNF chromatin-remodeling complexes are plausible candidates based on mouse knockout studies demonstrating a combined requirement for the BRG1 and BRM catalytic subunits in adult cardiomyocytes. Brg1/Brm double mutants exhibit metabolic and mitochondrial defects and are not viable although their cause of death has not been ascertained.
  
  
  
  To determine the cause of death of Brg1/Brm double-mutant mice, to test the hypothesis that BRG1 and BRM are required for cardiac contractility, and to identify relevant downstream target genes.
  
  
  
  A tamoxifen-inducible gene-targeting strategy utilizing αMHC-Cre-ERT was implemented to delete both SWI/SNF catalytic subunits in adult cardiomyocytes. Brg1/Brm double-mutant mice were monitored by echocardiography and electrocardiography, and they underwent rapidly progressive ventricular dysfunction including conduction defects and arrhythmias that culminated in heart failure and death within 3weeks. Mechanistically, BRG1/BRM repressed c-Myc expression, and enforced expression of a DOX-inducible c-MYC trangene in mouse cardiomyocytes phenocopied the ventricular conduction defects observed in Brg1/Brm double mutants. BRG1/BRM and c-MYC had opposite effects on the expression of cardiac conduction genes, and the directionality was consistent with their respective loss- and gain-of-function phenotypes. To support the clinical relevance of this mechanism, BRG1/BRM occupancy was diminished at the same target genes in human heart failure cases compared to controls, and this correlated with increased c-MYC expression and decreased CX43 and SCN5A expression.
  
  
  
  BRG1/BRM and c-MYC have an antagonistic relationship regulating the expression of cardiac conduction genes that maintain contractility, which is reminiscent of their antagonistic roles as a tumor suppressor and oncogene in cancer.
authors.affiliation: McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA; Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: monte_willis@med.unc.edu.
authors.forename: Monte S
authors.initials: MS
authors.lastname: Willis
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Darcy Wood
authors.initials: DW
authors.lastname: Holley
authors.affiliation: McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Zhongjing
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong University, 250021 Jinan, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Quintana
authors.affiliation: McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Jensen
authors.affiliation: Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong University, 250021 Jinan, PR China.
authors.forename: Manasi
authors.initials: M
authors.lastname: Tannu
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Parker
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Harrington Discovery Institute, University Hospitals Harrington Heart & Vascular Institute, Cleveland, OH 44106, USA.
authors.forename: Darwin
authors.initials: D
authors.lastname: Jeyaraj
authors.affiliation: Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Harrington Discovery Institute, University Hospitals Harrington Heart & Vascular Institute, Cleveland, OH 44106, USA.
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Jain
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Wolfram
authors.affiliation: Department of Biology, The University of Texas at San Antonio, San Antonio, TX 78249, USA. Electronic address: hyoung-gon.lee@utsa.edu.
authors.forename: Hyoung-Gon
authors.initials: HG
authors.lastname: Lee
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: Scott_Bultman@med.unc.edu.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Bultman
mesh_terms: D000818:Animals; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004562:Electrocardiography; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006329:Heart Conduction System; D006333:Heart Failure / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009200:Myocardial Contraction / Q000235:genetics; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; C499503:Smarca2 protein, mouse; D014157:Transcription Factors; C513194:Smarca4 protein, mouse; D004265:DNA Helicases
keywords: Arrhythmias; BRG1; BRM; Bradycardia; Cardiac connexins; Cardiomyocyte conduction; Heart failure; SWI/SNF; c-MYC