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

- Mouse BRG1 and BRM functionally compensate in adult cardiomyocytes as opposed to fetal cardiomyocytes, where BRG1 is essential but BRM is dispensable.
- BRG1 and BRM regulate the expression of cardiac conduction genes to prevent arrhythmias, heart failure, and death.
- BRG1 and BRM regulate the expression of downstream target genes both directly and indirectly via the activation of cardiogenic transcription factors and inhibition of c-Myc.
- The phenotype of the BRG1/BRM double mutant mouse model is phenocopied by inducible overexpression of c-Myc.
- Human heart failure cases exhibit increased expression of c-Myc, diminished BRG1/BRM occupancy of conduction genes, and decreased conduction gene expression.

RationaleThe 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.ObjectiveTo 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 resultsA 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.ConclusionBRG1/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.