A Pliable Mediator Acts as a Functional Rather Than an Architectural Bridge between Promoters and Enhancers.
A Pliable Mediator Acts as a Functional Rather Than an Architectural Bridge between Promoters and Enhancers.
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DOI：
10.1016/j.cell.2019.07.011
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发表时间：
2019-08-22
期刊：
影响因子：
64.5
通讯作者：
Casellas R
中科院分区：
文献类型：
--
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
虽然介体在真核生物转录中起着关键作用，但对其作用机制知之甚少。这项研究结合了CRISPR-Cas9基因筛选、降解决定子测定、Hi-C和cryo-EM来剖析哺乳动物介导子（mMED）的功能和结构。在B、T和ES细胞中的缺失分析确定了PolII募集全基因组所需的基本亚基的核心。相反，非必需亚基的丢失主要影响与多个增强子连接的启动子。然而，与目前的模型相反，mMED和PolII不适合物理地束缚调控DNA，这是一种需要结构蛋白的拓扑活性。Cryo-EM分析揭示了一个保守的核心，非必需亚基增加了Tail模块的结构复杂性，Tail模块是一个主要的转录因子靶标。尾结构的变化显着增加PolII和激酶模块的相互作用。我们建议，调解人的结构柔韧性，使其能够整合和传输调节信号，并作为一个功能，而不是建筑桥梁，启动子和增强子之间。介体促进和控制增强子和启动子之间的相互作用，但其本身不是系链这些元件所必需的。
While Mediator plays a key role in eukaryotic transcription, little is known about its mechanism of action. This study combines CRISPR-Cas9 genetic screens, degron assays, Hi-C, and cryo-EM to dissect the function and structure of mammalian Mediator (mMED). Deletion analyses in B, T and ES cells identified a core of essential subunits required for PolII recruitment genome-wide. Conversely, loss of non-essential subunits mostly affects promoters linked to multiple enhancers. Contrary to current models however, mMED and PolII are dispensable to physically tether regulatory DNA, a topological activity requiring architectural proteins. Cryo-EM analysis revealed a conserved core, with non-essential subunits increasing structural complexity of the Tail module, a primary transcription factor target. Changes in Tail structure markedly increase PolII and kinase module interactions. We propose that Mediator’s structural pliability enables it to integrate and transmit regulatory signals and act as a functional, rather than an architectural bridge, between promoters and enhancers. Mediator promotes and controls interactions between enhancers and promoters, but is not itself necessary to tether these elements.
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影响因子：
16.8
作者：
通讯作者：
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
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通讯作者：
Huber W
影响因子：
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作者：
Esnault, Cyril;Ghavi-Helm, Yad;Werner, Michel
通讯作者：
Werner, Michel
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
GDown1与RNA聚合酶II的功能关联，该聚合酶II有证明在人类基因上。
影响因子：
16
作者：
Cheng, Bo;Li, Tiandao;Rahl, Peter B.;Adamson, Todd E.;Loudas, Nicholas B.;Guo, Jiannan;Varzavand, Katayoun;Cooper, Jeffrey J.;Hu, Xiaopeng;Gnatt, Averell;Young, Richard A.;Price, David H.
通讯作者：
Price, David H.