Pathologic gene expression is a hallmark of DCM. Mice carrying a human DCM mutation in phospholamban (PLN) develop fibrosis, DCM and premature death. Temporal RNAseq and pathway analysis in PLN mice identified activation of pro-fibrotic gene expression as a key early driver of DCM. Recently, the bromodomain and extraterminal (BET) family of epigenetic reader proteins has been identified as a key regulator 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 genetic DCM. PLN and age-matched wild type (WT) mice were treated with the BET inhibitor JQ1 or vehicle from 8 (preDCM) to 20-weeks-of-age (advanced DCM). Vehicle-treated PLN mice developed DCM with severely reduced LV function, negative remodeling and LV hypertrophy, which was blunted with JQ1 (fractional shortening 15±3% vs 27±3%, p=7x10; LV end diastolic diameter 4.5±0.3mm vs. 3.9±0.3mm, p=1x10; LV mass 99±12mg vs. 86±13mg, p=1x10; n=15). In a separate cohort of mice treated beyond 20-weeks of age, JQ1 prolonged survival by 25% (p=0.009). JQ1 treatment also reduced cardiac fibrosis 3-fold (5.8% vs. 18.3% vehicle, p=4x10; n=3). Cardiac fibroblast proliferation was decreased 26% by JQ1 as assessed by 5-ethynyl-2’-deoxyuridine (EdU) incorporation (p=1x10; n=4). Integrated RNAseq analyses revealed temporal gene expression changes that were inhibited by JQ1. Notably, JQ1 treatment selectively inhibited stress-induced pathologic gene networks including TGFβ and innate immune signaling both in preDCM as well as advanced DCM stages. BET inhibition also prevented the shift in metabolic gene expression programs that is characteristic of advanced DCM and heart failure (HF). Interestingly, this occurred via a peroxisome proliferator-activated receptor independent mechanism. These data demonstrate that BETs are distal signaling integrators that control sequential pathologic gene expression programs longitudinally in DCM. BET inhibition substantially slowed disease progression and prolonged survival in this model of chronic DCM, and thereby provides a rationale for targeting epigenomic regulation as a therapeutic strategy for the treatment of human HF.