Epigenomic Control of Cardiac Fibrosis by Bet Bromodomain Proteins in Dilated Cardiomyopathy

Pathologic gene expression is a hallmark of DCM. Mice carrying a human DCM mutation in phospholamban (PLN R9C ) develop fibrosis, DCM, HF and premature death. RNAseq showed fibrotic gene expression to be a key early driver of DCM in PLN R9C mice. Recently, bromodomain and extraterminal (BET) epigenetic reader proteins have been identified as key regulators of pathologic gene expression in the heart. Using a chemical genetic strategy, we studied the role of BET proteins on the temporal regulation of gene expression in DCM. PLN R9C and age-matched wild type (WT) mice were treated longitudinally with the BET inhibitor JQ1 or vehicle. Vehicle-treated PLN R9C mice developed progressive DCM with reduced LV function, chamber dilation and LV hypertrophy; this was blunted with JQ1 (fractional shortening 15±3% vs. 27±3%, p Ppargc1a . BETs are more highly expressed in cardiac non-myocytes, suggesting cell compartment-specific effects in the heart. To test this, separate cardiac non-myocyte and cardiomyocyte populations were isolated from JQ1 or vehicle-treated mice with DCM. In non-myocytes JQ1 uniformly suppressed expression of genes driving pro-fibrotic and inflammatory signaling networks, including TGFβ and NF-κB (p R9C mice were altered with JQ1, indicating a predominant effect on cardiac non-myocytes. In summary, BET inhibition delayed fibrosis, blunted negative remodeling and prolonged survival in this model of chronic HF by altering gene expression programs in the cardiac non-myocyte population. These data confirm BETs as critical distal signaling integrators that control sequential activation of pathologic gene networks longitudinally in DCM, and provide a rationale for targeting epigenomic regulation as a therapeutic strategy for the treatment of human HF.