BRD4 (Bromodomain-Containing Protein 4) Interacts with GATA4 (GATA Binding Protein 4) to Govern Mitochondrial Homeostasis in Adult Cardiomyocytes

作者：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, Franco Felix, Juan A. Pérez-Bermejo, Qiaohong Wang, Li Li, Parisha P. Shah, Saptarsi M. Haldar, Rajan Jain, Deepak Srivastava · 发表于：Circulation · 年份：2020 · DOI：10.1161/circulationaha.120.047753 · 被引用次数：55 · 研究领域：Protein Degradation and Inhibitors、Chromatin Remodeling and Cancer、Genomics and Chromatin Dynamics

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-determin...