The Role of BRD4 in Cardiac Specification

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Summary Statement Cardiovascular disease remains the leading cause of death in the United States. One emerging long-term strategy for patients with congestive heart failure focuses on cellular regeneration. Efforts include boosting the function of existing cardiac myocytes, introducing immature myocytes into failing hearts, and even introducing electrically insulated patches of myocardium. All of these efforts require a highly-detailed understanding of the molecular determinants that drive myocyte lineage specification and differentiation and the mechanistic basis by which these factors regulate lineage specific gene expression cascades. Landmark studies have revealed a critical role for the Bromodomain extraterminal domain (BET) protein Brd4 in regulating lineage specific gene programs by recognizing or reading areas of the genome marked by specific modifications. In addition, studies abrogating BET protein function in murine models of heart failure have demonstrated promising results, by modulating lineage specific function. However, the normal role of BET proteins, specifically Brd4, has not been elucidated during cardiac development. Our data implicates a critical role for Brd4 during cardiac development, specifically by transcriptionally activating genes poised for expression upon lineage adoption. We seek to define the exact programs activated by Brd4 during cardiac development. In addition, our studies seek to understand if cardiac progenitor cells are rendered vulnerable to adopting aberrant cell fates upon loss of activation cues (via loss of Brd4). Our work will provide essential insight into how Brd4 drives cardiac lineage specification, ultimately allowing for manipulation of this process to generate cell types of interest. Defining the molecular pathways which regulate myogenesis will undoubtedly shape emerging novel therapeutics and regenerative strategi