1] Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA. [2] Program in Genomics of Differentiation, National Institutes of Child Health and Human Development, Bethesda, Maryland, USA.
Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland, USA.
Nat Struct Mol Biol. 2014 Dec;21(12):1047-57. doi: 10.1038/nsmb.2912. Epub 2014 Nov 10.
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 RNA polymerase II (Pol II) from promoter-proximal pausing. We show that BRD4 occupies widespread genomic regions in mouse cells and directly stimulates elongation of both protein-coding transcripts and noncoding enhancer RNAs (eRNAs), in a manner dependent on bromodomain function. BRD4 interacts with elongating Pol II complexes and assists Pol II in progression through hyperacetylated nucleosomes by interacting with acetylated histones via bromodomains. On active enhancers, the BET inhibitor JQ1 antagonizes BRD4-associated eRNA synthesis. Thus, BRD4 is involved in multiple steps of the transcription hierarchy, primarily by facilitating transcript elongation both at enhancers and on gene bodies independently of P-TEFb.
小分子 BET 抑制剂干扰乙酰化组蛋白与 BET 家族蛋白的溴结构域之间的表观遗传相互作用,包括 BRD4,并通过靶向促进癌症的基因强烈抑制恶性细胞的生长。BRD4 与暂停释放因子 P-TEFb 相互作用,并被提议从启动子近端暂停释放 RNA 聚合酶 II (Pol II)。我们表明 BRD4 在小鼠细胞中占据广泛的基因组区域,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,这种方式依赖于溴结构域的功能。BRD4 与延伸的 Pol II 复合物相互作用,并通过溴结构域与乙酰化组蛋白相互作用,协助 Pol II 通过超乙酰化核小体进行进展。在活性增强子上,BET 抑制剂 JQ1 拮抗 BRD4 相关的 eRNA 合成。因此,BRD4 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独立于 P-TEFb 促进转录本的延伸。
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