BET Epigenetic Reader Proteins in Cardiovascular Transcriptional Programs.
BET Epigenetic Reader Proteins in Cardiovascular Transcriptional Programs.
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在心血管转录程序中赌注表观遗传读取器蛋白。
DOI：
10.1161/circresaha.120.315929
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发表时间：
2020-04-24
影响因子：
20.1
通讯作者：
Plutzky J
中科院分区：
文献类型：
--
作者：
Borck PC;Guo LW;Plutzky J
表观遗传机制涉及组蛋白修饰的放置（“写入”）或去除（“擦除”），使常染色质转变为转录所需的开放、活化的染色质状态。第三种研究较少的表观遗传途径涉及一旦放置这些特定组蛋白标记的“阅读”。包含溴结构域和额外末端的蛋白质家族（BET），其包括BRD 2、BRD 3、BRD 4和睾丸限制性BRDT，是表观遗传阅读器蛋白，其结合组蛋白尾部上的特定乙酰化赖氨酸残基，在那里它们促进转录复合物的组装，所述转录复合物包括转录因子和转录机器如RNA聚合酶II。如本文所述，相当多的最新数据确立了BET作为血管细胞（如内皮细胞和血管平滑肌细胞）、心肌细胞和炎性细胞（如单核细胞/巨噬细胞）中诱导转录程序的新决定因素，这些表观遗传阅读器蛋白将近端刺激偶联到染色质的细胞环境，在超级增强子调控区起作用以指导基因表达。BET抑制，包括使用特定的化学BET抑制剂如JQ 1，在心血管环境中具有许多体内报道的效果，如减少动脉粥样硬化、血管生成、内膜增生、肺动脉高压和心脏肥大。同时，内皮细胞、脂肪细胞和其他地方的数据表明，BET也有助于在基础条件下调节基因表达。在心血管环境中的研究已经强调BET作用作为控制分化、细胞身份和细胞状态转变中的基因表达的手段，无论是生理的还是病理的，适应性的还是适应不良的。虽然不同的BET抑制剂正在寻求作为肿瘤学的治疗方法，但一项研究BET抑制剂RVX-208（现称为apabetalone）的大型前瞻性临床心血管结局研究已经完成。独立于这种特定的代理和这一个试验或许多悬而未决的问题，BET已经成为参与心血管健康和疾病中协调转录程序执行的新型表观遗传参与者。
Epigenetic mechanisms involve the placing (‘writing’) or removal (‘erasing’) of histone modifications that allows euchromatin to transition to the open, activated chromatin state necessary for transcription. A third, less studied epigenetic pathway involves the ‘reading’ of these specific histone marks once placed. The bromodomain and extra-terminal containing protein family (BETs), which includes BRD2, BRD3, BRD4 and the testis-restricted BRDT, are epigenetic reader proteins that bind to specific acetylated lysine residues on histone tails where they facilitate the assembly of transcription complexes including transcription factors and transcriptional machinery like RNA Polymerase II. As reviewed here, considerable recent data establishes BETs as novel determinants of induced transcriptional programs in vascular cells, like endothelial cells and vascular smooth muscle cells, cardiac myocytes and inflammatory cells, like monocyte/macrophages, cellular settings where these epigenetic reader proteins couple proximal stimuli to chromatin, acting at super-enhancer regulatory regions to direct gene expression. BET inhibition, including the use of specific chemical BET inhibitors like JQ1, has many reported effects in vivo in the cardiovascular setting, like decreasing atherosclerosis, angiogenesis, intimal hyperplasia, pulmonary arterial hypertension and cardiac hypertrophy. At the same time, data in endothelial cells, adipocytes and elsewhere suggests BETs also help regulate gene expression under basal conditions. Studies in the cardiovascular setting have highlighted BET action as a means of controlling gene expression in differentiation, cell identity and cell state transitions, whether physiologic or pathologic, adaptive or maladaptive. While distinct BET inhibitors are being pursued as therapies in oncology, a large prospective clinical cardiovascular outcome study investigating the BET inhibitor RVX-208 (now called apabetalone) has already been completed. Independent of this specific agent and this one trial or the numerous unanswered questions that remain, BETs have emerged as novel epigenetic players involved in the execution of coordinated transcriptional programs in cardiovascular health and disease.