BRD4 assists elongation of both coding and enhancer RNAs by interacting with acetylated histones.
BRD4 assists elongation of both coding and enhancer RNAs by interacting with acetylated histones.
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DOI：
10.1038/nsmb.2912
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发表时间：
2014-12
影响因子：
16.8
通讯作者：
Ozato K
中科院分区：
文献类型：
--
作者：
Kanno T;Kanno Y;LeRoy G;Campos E;Sun HW;Brooks SR;Vahedi G;Heightman TD;Garcia BA;Reinberg D;Siebenlist U;O'Shea JJ;Ozato K
小分子BET抑制剂干扰乙酰化组蛋白和BET家族蛋白（包括BRD 4）的溴结构域之间的表观遗传相互作用，并且它们通过靶向促癌基因有效抑制恶性细胞的生长。BRD 4与暂停释放因子P-TEFb相互作用，并且已经提出从启动子近端暂停释放Pol II。我们发现，BRD 4占据了小鼠细胞中广泛的基因组区域，并直接刺激蛋白质编码转录本和非编码增强子RNA（eRNA）的延伸，这取决于溴结构域的功能。BRD 4与延长Pol II复合物物理相互作用，并通过溴结构域与乙酰化组蛋白相互作用，通过超乙酰化核小体辅助Pol II进展。在活性增强剂上，BET抑制剂JQ 1拮抗BRD 4相关的eRNA合成。因此，BRD 4参与转录层次的多个步骤，主要是通过在增强子和基因体上辅助转录延长。
Small-molecule BET inhibitors interfere with the epigenetic interactions between acetylated histones and the bromodomains of the BET family proteins, including BRD4, and they potently inhibit growth of malignant cells by targeting cancer-promoting genes. BRD4 interacts with the pause-release factor P-TEFb, and has been proposed to release Pol II from promoter-proximal pausing. We show that BRD4 occupied widespread genomic regions in mouse cells, and directly stimulated elongation of both protein-coding transcripts and non-coding enhancer RNAs (eRNAs), dependent on the function of bromodomains. BRD4 interacted physically with elongating Pol II complexes, and assisted Pol II progression through hyper-acetylated nucleosomes by interacting with acetylated histones via bromodomains. On active enhancers, the BET inhibitor JQ1 antagonized BRD4-associated eRNA synthesis. Thus, BRD4 is involved in multiple steps of the transcription hierarchy, primarily by assisting transcript elongation both at enhancers and on gene bodies.