Regulation of Chromatin Signaling in Heart Failure by BET Bromodomain Proteins

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 DESCRIPTION (provided by applicant): Despite current standard of care, a diagnosis of heart failure (HF) is associated with poor quality-of-life and a 5-year mortality approaching 50%. In light of this urgent unmet need, the elucidation of novel mechanisms involved in HF pathogenesis holds promise for identifying new therapies for this prevalent and deadly disease. The PIs of this application were the first to illustrate a crucial role for a conserved family of acetyl-lysine "reader" proteins (BET bromodomains) in the transcriptional control of pathological cardiac hypertrophy and HF. Importantly, these studies leveraged the use of JQ1, a first-in-class, specific small molecule inhibitor of BET bromodomains. This multi-PI application seeks to vertically advance our understanding of how aberrant chromatin dependent signal transduction (via the BET family member BRD4) drives pathologic cardiac remodeling. Our long-term objective is to develop BET bromodomain inhibition as a novel therapeutic strategy in HF. Exciting preliminary studies demonstrate that BRD4 mediates cardiomyocyte (CM) hypertrophy in vitro and that BET inhibition with JQ1 potently suppresses the development of pressure-overload mediated cardiac hypertrophy in mice. Mechanistically, we demonstrate that BRD4 occupies active enhancers in the adult mouse heart, recruits PTEF-b activity to transcriptional start sites, and triggers pause-release of RNA Polymerase II to activate genes critical for HF pathogenesis. Intriguingly, we demonstrate that pathologic stress leads to specific accumulation of BRD4 protein in CMs without any increase in Brd4 mRNA. Finally, we demonstrate that class I HDACs, which are generally pro-hypertrophic, are specifically required for BRD4 protein accumulation. Based on this rationale, this proposal will test the central hypothesis that BRD4 functions as a nodal transcriptional regulator of pathological cardiac remodeling that can be pharmacologically targeted in vivo. Guided by strong preliminary data, this hypothesis will be tested by pursuing three robust specific aims: (1) Elucidate the effects of BET inhibition in clinically relevant models of HF and during physiological cardiac plasticity; (2) Dissect the transcriptional mechanisms by which BRD4 drives dynamic enhancer remodeling, chromatin-dependent signal transduction, and selective gene control during cardiac stress; (3) Define the mechanisms by which HDACs crosstalk with BET proteins to integrate upstream signals with pro-hypertrophic gene expression in the heart. The proposed research is significant because it seeks to develop pharmacologic BET bromodomain inhibition as a novel therapeutic strategy in HF, and therefore addresses an enormous unmet clinical need. Our proposal is highly innovative because we successfully "drug" pathologic myocardial transcription and remodeling via an unprecedented approach. Given the synergistic expertise of our consortium, we envision that sustained contributions from our highly-collaborative group will pave the way for the development of novel "epigenetic therapies" for cardiovascular disease.