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

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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 3 weeks. 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.

Original languageEnglish (US)
Pages (from-to)99-109
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume105
DOIs
StatePublished - Apr 1 2017

Keywords

  • Arrhythmias
  • BRG1
  • BRM
  • Bradycardia
  • Cardiac connexins
  • Cardiomyocyte conduction
  • Heart failure
  • SWI/SNF
  • c-MYC

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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