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Updated: Mar 7, 2026
Isolation, Culture, and Functional Characterization of Adult Mouse Cardiomyoctyes
Published on: September 24, 2013
BRG1 and BRM function antagonistically with c-MYC in adult cardiomyocytes to regulate conduction and contractility
Monte S Willis1, Darcy Wood Holley2, Zhongjing Wang3
1McAllister 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.
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.
Insights
SWI/SNF chromatin remodelers BRG1/BRM are essential for cardiac function. Their loss in adult cardiomyocytes causes heart failure by increasing oncogene c-Myc, leading to conduction defects and death.
Area of Science:
- Epigenetics and chromatin remodeling
- Cardiovascular biology
- Molecular mechanisms of heart failure
Background:
- Heart failure involves contractile dysfunction with altered biological processes.
- Epigenetic mechanisms contributing to heart failure remain largely unknown.
- SWI/SNF chromatin-remodeling complexes, particularly BRG1 and BRM, are implicated in cardiomyocyte function.
Purpose of the Study:
- Determine the cause of death in Brg1/Brm double-mutant mice.
- Investigate the role of BRG1 and BRM in cardiac contractility.
- Identify downstream target genes regulated by BRG1/BRM in the heart.
Main Methods:
- Utilized a tamoxifen-inducible gene-targeting strategy in adult cardiomyocytes (αMHC-Cre-ERT).
- Monitored Brg1/Brm double-mutant mice using echocardiography and electrocardiography.
- Analyzed gene expression and chromatin occupancy in mouse models and human heart failure samples.
Main Results:
- Brg1/Brm deletion in adult cardiomyocytes led to rapid ventricular dysfunction, conduction defects, arrhythmias, and heart failure within 3 weeks.
- BRG1/BRM normally repress c-Myc expression; enforced c-Myc expression phenocopied conduction defects.
- BRG1/BRM and c-Myc antagonistically regulate cardiac conduction genes (e.g., CX43, SCN5A); reduced BRG1/BRM and increased c-Myc were observed in human heart failure.
Conclusions:
- BRG1/BRM and c-Myc have an antagonistic regulatory relationship over cardiac conduction genes essential for contractility.
- This antagonistic relationship mirrors their roles as tumor suppressor and oncogene in cancer.
- Epigenetic regulation by SWI/SNF complexes is critical for maintaining cardiac function and preventing heart failure.
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