Epigenetic Reader BRD4 (Bromodomain-Containing Protein 4) Governs Nucleus-Encoded Mitochondrial Transcriptome to Regulate Cardiac Function.
Epigenetic Reader BRD4 (Bromodomain-Containing Protein 4) Governs Nucleus-Encoded Mitochondrial Transcriptome to Regulate Cardiac Function.
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DOI：
10.1161/circulationaha.120.047239
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发表时间：
2020-12-15
期刊：
影响因子：
37.8
通讯作者：
Hill JA
中科院分区：
文献类型：
--
作者：
Kim SY;Zhang X;Schiattarella GG;Altamirano F;Ramos TAR;French KM;Jiang N;Szweda PA;Evers BM;May HI;Luo X;Li H;Szweda LI;Maracaja-Coutinho V;Lavandero S;Gillette TG;Hill JA
BET （Bromodomain and Extra-Terminal）表观遗传解读蛋白，特别是BRD4，已成为包括癌症和心血管疾病在内的许多病理疾病的潜在治疗靶点。小分子BET蛋白抑制剂，如JQ1，已经在临床前模型中证明了逆转心脏肥厚和心力衰竭的疗效。然而，尚未进行遗传学研究来阐明BET蛋白在心脏中的生物学作用，以验证药理学发现并揭示潜在的药理学副作用。通过设计心肌细胞特异性BRD4（含溴结构域蛋白4）敲除小鼠，我们研究了BRD4在心脏病理生理中的作用。我们进行了功能、转录组学和线粒体分析，以评估BRD4在发育和成熟心脏中的功能。与药物抑制不同，BRD4蛋白的缺失引发心肌功能的进行性下降，最终导致扩张型心肌病。BRD4基因敲除小鼠心脏组织的转录组分析发现了线粒体能量产生和体内平衡所必需的基因的早期和特异性破坏。对这些心脏分离线粒体的功能分析证实，BRD4消融引发了线粒体电子传递链蛋白表达和活性的显著变化。计算分析确定了参与brd4调控转录组的候选转录因子。特别是，代谢基因调控的关键核受体ESRRα（雌激素相关受体α）在brd4调控的线粒体基因启动子中富集。总的来说，我们描述了BRD4在调节心肌细胞线粒体稳态中的先前未被认识到的作用，观察到其功能对于维持正常的心功能是不可或缺的。
BET (Bromodomain and Extra-Terminal) epigenetic reader proteins, in particular BRD4, have emerged as potential therapeutic targets in a number of pathological conditions, including cancer and cardiovascular disease. Small molecule BET protein inhibitors, such as JQ1, have demonstrated efficacy in reversing cardiac hypertrophy and heart failure in preclinical models. Yet, genetic studies elucidating the biology of BET proteins in the heart have not been conducted to validate pharmacological findings and unveil potential pharmacological side effects. By engineering a cardiomyocyte-specific BRD4 (bromodomain-containing protein 4) knockout mouse, we investigated the role of BRD4 in cardiac pathophysiology. We performed functional, transcriptomic, and mitochondrial analysis to evaluate BRD4 function in developing and mature hearts. Unlike pharmacological inhibition, loss of BRD4 protein triggered progressive declines in myocardial function, culminating in dilated cardiomyopathy. Transcriptome analysis of BRD4 knockout mouse heart tissue identified early and specific disruption of genes essential to mitochondrial energy production and homeostasis. Functional analysis of isolated mitochondria from these hearts confirmed that BRD4 ablation triggered significant changes in mitochondrial electron transport chain protein expression and activity. Computational analysis identified candidate transcription factors participating in the BRD4-regulated transcriptome. In particular, ESRRα (estrogen-related receptor alpha), a key nuclear receptor in metabolic gene regulation, was enriched in promoters of BRD4-regulated mitochondrial genes. In aggregate, we describe a previously unrecognized role for BRD4 in regulating cardiomyocyte mitochondrial homeostasis, observing that its function is indispensable to the maintenance of normal cardiac function.