Arun Padmanabhan1,2, Michael Alexanian1, Ricardo Linares-Saldana3, Rajan Jain3, Deepak Srivastava1,4,5,6, Bárbara González-Terán1, Gaia Andreoletti7, Yu Huang1, Andrew J Connolly8, Wonho Kim3, Austin Hsu1, Qiming Duan1, Sarah A B Winchester1, Franco Felix1, Juan A Perez-Bermejo1, Qiaohong Wang3, Li Li3, Parisha P Shah3, Saptarsi M Haldar1,2. 1. Gladstone Institute of Cardiovascular Disease, San Francisco, CA (A.P., M.A., B.G.-T., Y.H., A.H., Q.D., S.A.B.W., F.F., J.A.P.-B., S.M.H., D.S.). 2. Division of Cardiology, Department of Medicine (A.P., S.M.H.), University of California, San Francisco. 3. Institute of Regenerative Medicine, Penn Cardiovascular Institute, Departments of Medicine and Cell and Developmental Biology, Perelman School of Medicine, Philadelphia, PA (R.L.-S., W.K., Q.W., L.L., P.P.S., R.J.). 4. Department of Pediatrics (D.S.), University of California, San Francisco. 5. Department of Biochemistry and Biophysics (D.S.), University of California, San Francisco. 6. Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA (D.S.). 7. Bakar Computational Health Sciences Institute (G.A.), University of California, San Francisco. 8. Department of Pathology (A.J.C.), University of California, San Francisco.
Abstract
BACKGROUND: Gene regulatory networks control tissue homeostasis and disease progression in a cell type-specific manner. Ubiquitously expressed chromatin regulators modulate these networks, yet the mechanisms governing how tissue specificity of their function is achieved are poorly understood. BRD4 (bromodomain-containing protein 4), a member of the BET (bromo- and extraterminal domain) family of ubiquitously expressed acetyl-lysine reader proteins, plays a pivotal role as a coactivator of enhancer signaling across diverse tissue types in both health and disease and has been implicated as a pharmacological target in heart failure. However, the cell-specific role of BRD4 in adult cardiomyocytes remains unknown. METHODS: We combined conditional mouse genetics, unbiased transcriptomic and epigenomic analyses, and classic molecular biology and biochemical approaches to understand the mechanism by which BRD4 in adult cardiomyocyte homeostasis. RESULTS: Here, we show that cardiomyocyte-specific deletion of Brd4 in adult mice leads to acute deterioration of cardiac contractile function with mutant animals demonstrating a transcriptomic signature characterized by decreased expression of genes critical for mitochondrial energy production. Genome-wide occupancy data show that BRD4 enriches at many downregulated genes (including the master coactivators Ppargc1a, Ppargc1b, and their downstream targets) and preferentially colocalizes with GATA4 (GATA binding protein 4), a lineage-determining cardiac transcription factor not previously implicated in regulation of adult cardiac metabolism. BRD4 and GATA4 form an endogenous complex in cardiomyocytes and interact in a bromodomain-independent manner, revealing a new functional interaction partner for BRD4 that can direct its locus and tissue specificity. CONCLUSIONS: These results highlight a novel role for a BRD4-GATA4 module in cooperative regulation of a cardiomyocyte-specific gene program governing bioenergetic homeostasis in the adult heart.
BACKGROUND: Gene regulatory networks control tissue homeostasis and disease progression in a cell type-specific manner. Ubiquitously expressed chromatin regulators modulate these networks, yet the mechanisms governing how tissue specificity of their function is achieved are poorly understood. BRD4 (bromodomain-containing protein 4), a member of the BET (bromo- and extraterminal domain) family of ubiquitously expressed acetyl-lysine reader proteins, plays a pivotal role as a coactivator of enhancer signaling across diverse tissue types in both health and disease and has been implicated as a pharmacological target in heart failure. However, the cell-specific role of BRD4 in adult cardiomyocytes remains unknown. METHODS: We combined conditional mouse genetics, unbiased transcriptomic and epigenomic analyses, and classic molecular biology and biochemical approaches to understand the mechanism by which BRD4 in adult cardiomyocyte homeostasis. RESULTS: Here, we show that cardiomyocyte-specific deletion of Brd4 in adult mice leads to acute deterioration of cardiac contractile function with mutant animals demonstrating a transcriptomic signature characterized by decreased expression of genes critical for mitochondrial energy production. Genome-wide occupancy data show that BRD4 enriches at many downregulated genes (including the master coactivators Ppargc1a, Ppargc1b, and their downstream targets) and preferentially colocalizes with GATA4 (GATA binding protein 4), a lineage-determining cardiac transcription factor not previously implicated in regulation of adult cardiac metabolism. BRD4 and GATA4 form an endogenous complex in cardiomyocytes and interact in a bromodomain-independent manner, revealing a new functional interaction partner for BRD4 that can direct its locus and tissue specificity. CONCLUSIONS: These results highlight a novel role for a BRD4-GATA4 module in cooperative regulation of a cardiomyocyte-specific gene program governing bioenergetic homeostasis in the adult heart.
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