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BRD4 Interacts with GATA4 to Govern Mitochondrial Homeostasis in Adult Cardiomyocytes

By Arun Padmanabhan, Michael Alexanian, Ricardo Linares-Saldana, Bárbara González-Terán, Gaia Andreoletti, Yu Huang, Andrew J. Connolly, Wonho Kim, Austin Hsu, Qiming Duan, Sarah A. B. Winchester, Saptarsi M Haldar, Rajan Jain, Deepak Srivastava

Posted 17 Apr 2020
bioRxiv DOI: 10.1101/2020.04.16.041806

Gene regulatory networks control tissue plasticity during basal homeostasis and disease 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, a member of the BET (Bromo- and Extra-Terminal 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 pharmacologic target in heart failure. However, the cell-specific role of BRD4 in adult cardiomyocytes remains unknown. 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 enriched for decreased expression of genes critical for mitochondrial energy production. Genome-wide occupancy data show that BRD4 enriches at many downregulated genes and preferentially co-localizes with GATA4, a lineage determining cardiac transcription factor not previously implicated in regulation of adult cardiac metabolism. Co-immunoprecipitation assays demonstrate that BRD4 and GATA4 form a complex in a bromodomain-independent manner, revealing a new interaction partner for BRD4 that has functional consequences for target transactivation and may allow for locus and tissue specificity. 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. ### Competing Interest Statement D.S. is scientific co-founder, shareholder and director of Tenaya Therapeutics. S.M.H. is an executive, officer, and shareholder of Amgen, Inc. and is a scientific co-founder and shareholder of Tenaya Therapeutics.

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