BRG1 and BRM function antagonistically with c-MYC in adult cardiomyocytes to regulate conduction and contractility

Monte S Willis; Darcy Wood Holley; Zhongjing Wang; Xin Chen; Megan Quintana; Brian C Jensen; Manasi Tannu; Joel Parker; Darwin Jeyaraj; Mukesh K Jain; Julie A Wolfram; Hyoung-Gon Lee; Scott J Bultman

doi:10.1016/j.yjmcc.2017.02.003

BRG1 and BRM function antagonistically with c-MYC in adult cardiomyocytes to regulate conduction and contractility

J Mol Cell Cardiol. 2017 Apr:105:99-109. doi: 10.1016/j.yjmcc.2017.02.003. Epub 2017 Feb 21.

Authors

Affiliations

¹ 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.
² Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
³ McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.
⁴ Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong University, 250021 Jinan, PR China.
⁵ McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
⁶ 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.
⁷ Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Harrington Discovery Institute, University Hospitals Harrington Heart & Vascular Institute, Cleveland, OH 44106, USA.
⁸ Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
⁹ Department of Biology, The University of Texas at San Antonio, San Antonio, TX 78249, USA. Electronic address: hyoung-gon.lee@utsa.edu.
¹⁰ 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.

Abstract

Rationale: 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.

Objective: 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.

Methods and results: 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.

Conclusion: 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.

Keywords: Arrhythmias; BRG1; BRM; Bradycardia; Cardiac connexins; Cardiomyocyte conduction; Heart failure; SWI/SNF; c-MYC.

Publication types

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

MeSH terms

Animals
DNA Helicases / genetics
DNA Helicases / metabolism*
Electrocardiography
Gene Expression Profiling
Gene Expression Regulation
Heart Conduction System*
Heart Failure / diagnosis
Heart Failure / genetics
Heart Failure / metabolism
Heart Failure / physiopathology
Humans
Mice
Mice, Transgenic
Mutation
Myocardial Contraction* / genetics
Myocytes, Cardiac / metabolism*
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Protein Binding
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism*
Transcription Factors / genetics
Transcription Factors / metabolism*

Substances

Nuclear Proteins
Proto-Oncogene Proteins c-myc
Smarca2 protein, mouse
Transcription Factors
Smarca4 protein, mouse
DNA Helicases

Abstract

Publication types

MeSH terms

Substances

Grants and funding