RNAs interact with BRD4 to promote enhanced chromatin engagement and transcription activation.
RNAs interact with BRD4 to promote enhanced chromatin engagement and transcription activation.
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DOI：
10.1038/s41594-018-0102-0
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发表时间：
2018-08
影响因子：
16.8
通讯作者：
Lauberth SM
中科院分区：
文献类型：
--
作者：
Rahnamoun H;Lee J;Sun Z;Lu H;Ramsey KM;Komives EA;Lauberth SM
溴结构域和末端外基序（BET）蛋白BRD 4通过其溴结构域（BD）在增强子和启动子处结合乙酰化组蛋白以调节转录延伸。在这里，我们揭示了在人类结直肠癌细胞中，BRD 4被募集到由突变型p53共同占据的增强子中，并支持增强子定向转录物（eRNA）的合成以响应慢性免疫信号。我们鉴定了BRD 4选择性地与由BRD 4结合增强子产生的eRNA结合。通过生物化学和生物物理特性，我们表明，BRD 4的BD合作作为对接网站的eRNA和BRD 2，BRD 3，BRDT，BRG 1和BRD 7的BD直接与eRNA相互作用。BRD 4-eRNA相互作用增加BRD 4与乙酰化组蛋白的结合，并促进增强BRD 4在特异性增强子处的募集，这增强了BRD 4的转录活性。这项工作强调了eRNA通过调节增强子相互作用和BRD 4的转录功能在基因调控中发挥直接作用的机制。
Bromodomain and extra-terminal motif (BET) protein BRD4 binds to acetylated histones at enhancers and promoters through its bromodomains (BDs) to regulate transcriptional elongation. Here, we reveal in human colorectal cancer cells that BRD4 is recruited to enhancers that are co-occupied by mutant p53 and support the synthesis of enhancer-directed transcripts (eRNAs) in response to chronic immune signaling. We identify that BRD4 selectively associates with eRNAs that are produced from BRD4 bound enhancers. Through biochemical and biophysical characterizations, we show that BRD4 BDs function cooperatively as docking sites for eRNAs and that the BDs of BRD2, BRD3, BRDT, BRG1, and BRD7 directly interact with eRNAs. BRD4-eRNA interactions increase BRD4 binding to acetylated histones and promote enhanced BRD4 recruitment at specific enhancers which augments BRD4 transcriptional activities. This work highlights a mechanism by which eRNAs play a direct role in gene regulation by modulating enhancer interactions and transcriptional functions of BRD4.
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影响因子：
16
作者：
Calo, Eliezer;Wysocka, Joanna
通讯作者：
Wysocka, Joanna
影响因子：
64.8
作者：
Heintzman, Nathaniel D.;Hon, Gary C.;Hawkins, R. David;Kheradpour, Pouya;Stark, Alexander;Harp, Lindsey F.;Ye, Zhen;Lee, Leonard K.;Stuart, Rhona K.;Ching, Christina W.;Ching, Keith A.;Antosiewicz-Bourget, Jessica E.;Liu, Hui;Zhang, Xinmin;Green, Roland D.;Lobanenkov, Victor V.;Stewart, Ron;Thomson, James A.;Crawford, Gregory E.;Kellis, Manolis;Ren, Bing
通讯作者：
Ren, Bing
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1038/nrm3949
发表时间：
2015-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Heinz S;Romanoski CE;Benner C;Glass CK
通讯作者：
Glass CK
影响因子：
64.8
作者：
Lai F;Gardini A;Zhang A;Shiekhattar R
通讯作者：
Shiekhattar R