BET Bromodomains Mediate Transcriptional Pause Release in Heart Failure [NRVM Expression]

Heart failure (HF) is driven via interplay between master regulatory transcription factors and dynamic alterations in chromatin structure. While pathologic gene transactivation in this context is known to be associated with recruitment of histone acetyl-transferases and local chromatin hyperacetylation, the role of epigenetic reader proteins in cardiac biology is unknown. We therefore undertook a first study of acetyl-lysine reader proteins, or bromodomains, in HF. Using a chemical genetic approach, we establish a central role for BET-family bromodomain proteins in gene control during HF pathogenesis. BET inhibition potently suppresses cardiomyocyte hypertrophy in vitro and pathologic cardiac remodeling in vivo. Integrative transcriptional and epigenomic analyses reveal that BET proteins function mechanistically as pause-release factors critical to activation of canonical master regulators and effectors that are central to HF pathogenesis and relevant to the pathobiology of failing human hearts. This study implicates epigenetic readers in cardiac biology and identifies BET co-activator proteins as therapeutic targets in HF.心力衰竭（Heart failure, HF）由主调控转录因子（master regulatory transcription factors）与染色质结构（chromatin structure）的动态改变之间的相互作用所驱动。尽管目前已知该病理情境下的病理性基因转录激活（pathologic gene transactivation）与组蛋白乙酰转移酶（histone acetyl-transferases）的招募及局部染色质高度乙酰化相关，但表观遗传阅读器蛋白（epigenetic reader proteins）在心脏生物学中的作用尚不明确。为此，我们开展了首项针对乙酰赖氨酸阅读器蛋白——即溴结构域（bromodomains）——在HF中功能的研究。通过化学遗传学方法（chemical genetic approach），我们证实BET家族溴结构域蛋白（BET-family bromodomain proteins）在心力衰竭发病过程的基因调控中发挥核心作用。BET抑制剂可在体外有效抑制心肌细胞肥大（cardiomyocyte hypertrophy），并在体内抑制病理性心脏重构（pathologic cardiac remodeling）。整合转录组与表观基因组分析（Integrative transcriptional and epigenomic analyses）显示，BET蛋白在机制上作为暂停释放因子（pause-release factors），对激活心力衰竭发病机制核心的经典主调控因子及效应因子至关重要，且这些因子与衰竭人类心脏的病理生物学（pathobiology）相关。本研究将表观遗传阅读器蛋白与心脏生物学建立了关联，并确定BET辅助激活蛋白可作为心力衰竭的治疗靶点（therapeutic targets）。