BET inhibition disrupts transcription but retains enhancer-promoter contact.
BET inhibition disrupts transcription but retains enhancer-promoter contact.
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DOI：
10.1038/s41467-020-20400-z
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发表时间：
2021-01-11
影响因子：
16.6
通讯作者：
Milne TA
中科院分区：
文献类型：
--
作者：
Crump NT;Ballabio E;Godfrey L;Thorne R;Repapi E;Kerry J;Tapia M;Hua P;Lagerholm C;Filippakopoulos P;Davies JOJ;Milne TA
增强子是一种DNA序列，能够对高等真核生物中的基因进行复杂的时间和组织特异性调控。虽然目前还不完全清楚增强子-启动子相互作用如何增加基因表达，但这种接近已经在多个系统的多个基因位点上观察到，并被认为是维持基因表达的关键。溴结构域、末端外结构域(BET)和介体蛋白已被证明能够形成相缩合物，并被认为是超级增强子功能所必需的。在这里，我们表明，用BET蛋白的抑制剂靶向细胞或BET蛋白溴域包含蛋白4(BRD4)的药物降解对转录有强烈的影响，但对增强子-启动子的相互作用影响很小。溶解相冷凝物减少了BRD4和介体在增强子上的结合，也可以强烈地影响基因转录，而不会破坏增强子-启动子的相互作用。这些结果表明，转录的激活和增强子-启动子相互作用的维持是分开的事件。我们的发现进一步表明，增强子-启动子的相互作用不依赖于高水平的BRD4和Mediator，并且可能由一系列复杂的因素维持，包括额外的激活复合体，在某些位置，CTCF和粘附素。BRD4和Mediator在调节增强子-启动子相互作用中的作用还知之甚少。在这里，作者发现，使用BET抑制剂或药物降解BRD4会扰乱转录，而对增强子-启动子的相互作用影响很小。
Enhancers are DNA sequences that enable complex temporal and tissue-specific regulation of genes in higher eukaryotes. Although it is not entirely clear how enhancer-promoter interactions can increase gene expression, this proximity has been observed in multiple systems at multiple loci and is thought to be essential for the maintenance of gene expression. Bromodomain and Extra-Terminal domain (BET) and Mediator proteins have been shown capable of forming phase condensates and are thought to be essential for super-enhancer function. Here, we show that targeting of cells with inhibitors of BET proteins or pharmacological degradation of BET protein Bromodomain-containing protein 4 (BRD4) has a strong impact on transcription but very little impact on enhancer-promoter interactions. Dissolving phase condensates reduces BRD4 and Mediator binding at enhancers and can also strongly affect gene transcription, without disrupting enhancer-promoter interactions. These results suggest that activation of transcription and maintenance of enhancer-promoter interactions are separable events. Our findings further indicate that enhancer-promoter interactions are not dependent on high levels of BRD4 and Mediator, and are likely maintained by a complex set of factors including additional activator complexes and, at some sites, CTCF and cohesin. The role of BRD4 and Mediator in regulating enhancer-promoter interactions is poorly understood. Here the authors find that treatment with BET inhibitors or pharmacological degradation of BRD4 disrupts transcription while having very little effect on enhancer-promoter interactions.
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影响因子：
64.5
作者：
El Khattabi L;Zhao H;Kalchschmidt J;Young N;Jung S;Van Blerkom P;Kieffer-Kwon P;Kieffer-Kwon KR;Park S;Wang X;Krebs J;Tripathi S;Sakabe N;Sobreira DR;Huang SC;Rao SSP;Pruett N;Chauss D;Sadler E;Lopez A;Nóbrega MA;Aiden EL;Asturias FJ;Casellas R
通讯作者：
Casellas R
影响因子：
16.8
作者：
通讯作者：
--
影响因子：
16
作者：
Cajigas I;Chakraborty A;Swyter KR;Luo H;Bastidas M;Nigro M;Morris ER;Chen S;VanGompel MJW;Leib D;Kohtz SJ;Martina M;Koh S;Ay F;Kohtz JD
通讯作者：
Kohtz JD
影响因子：
64.5
作者：
Deng W;Lee J;Wang H;Miller J;Reik A;Gregory PD;Dean A;Blobel GA
通讯作者：
Blobel GA
模因套件：用于发现和搜索的工具。
影响因子：
14.9
作者：
Bailey TL;Boden M;Buske FA;Frith M;Grant CE;Clementi L;Ren J;Li WW;Noble WS
通讯作者：
Noble WS