Building regulatory landscapes reveals that an enhancer can recruit cohesin to create contact domains, engage CTCF sites and activate distant genes.
Building regulatory landscapes reveals that an enhancer can recruit cohesin to create contact domains, engage CTCF sites and activate distant genes.
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DOI：
10.1038/s41594-022-00787-7
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发表时间：
2022-06
影响因子：
16.8
通讯作者：
de laat, Wouter
中科院分区：
文献类型：
--
作者：
Rinzema, Niels J.;Sofiadis, Konstantinos;Tjalsma, Sjoerd J. D.;Verstegen, Marjon J. A. M.;Oz, Yuva;Valdes-Quezada, Christian;Felder, Anna-Karina;Filipovska, Teodora;van der Elst, Stefan;dos Ramos, Zaria de Andrade;Han, Ruiqi;Krijger, Peter H. L.;de laat, Wouter
发育基因表达通常由称为增强子的远端调控DNA元件控制。远距离增强子作用限于两侧为CTCF相关边界并通过粘着蛋白染色质环挤出形成的结构染色体结构域。为了更好地理解增强子、基因和CTCF边界如何共同形成结构域并控制表达，我们使用了自下而上的方法，在非活性染色质中构建了一系列活性调控景观。我们在这里证明，基因转录水平和活性随着时间的推移而降低增强子距离的增加。增强子募集粘附素以刺激结构域形成并在环形成中接合侧翼CTCF位点。它需要cohesin专门用于激活远端基因，而不是近端基因，附近的CTCF边界支持有效的远程增强子作用。我们的工作支持增强子的双重活性模型：其经典的作用是刺激转录起始和从靶基因启动子延伸，以及招募粘连蛋白以创建染色体结构域、CTCF位点参与染色质循环和激活远端靶基因。在这里，作者在非活性染色质环境中构建了不同的调控景观，并观察到增强子既可以在靶基因启动子处发挥刺激转录起始和延伸的经典作用，又可以招募粘附素以创建接触结构域，接合CTCF位点并激活远端基因。
Developmental gene expression is often controlled by distal regulatory DNA elements called enhancers. Distant enhancer action is restricted to structural chromosomal domains that are flanked by CTCF-associated boundaries and formed through cohesin chromatin loop extrusion. To better understand how enhancers, genes and CTCF boundaries together form structural domains and control expression, we used a bottom-up approach, building series of active regulatory landscapes in inactive chromatin. We demonstrate here that gene transcription levels and activity over time reduce with increased enhancer distance. The enhancer recruits cohesin to stimulate domain formation and engage flanking CTCF sites in loop formation. It requires cohesin exclusively for the activation of distant genes, not of proximal genes, with nearby CTCF boundaries supporting efficient long-range enhancer action. Our work supports a dual activity model for enhancers: its classic role of stimulating transcription initiation and elongation from target gene promoters and a role of recruiting cohesin for the creation of chromosomal domains, the engagement of CTCF sites in chromatin looping and the activation of distal target genes. Here the authors build different regulatory landscapes in an inactive chromatin environment and observe that enhancers can both carry out their classic role of stimulating transcription initiation and elongation at target gene promoters and recruit cohesin to create contact domains, engage CTCF sites and activate distant genes.
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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：
64.5
作者：
Haarhuis JHI;van der Weide RH;Blomen VA;Yáñez-Cuna JO;Amendola M;van Ruiten MS;Krijger PHL;Teunissen H;Medema RH;van Steensel B;Brummelkamp TR;de Wit E;Rowland BD
通讯作者：
Rowland BD
影响因子：
7.7
作者：
Freire-Pritchett P;Schoenfelder S;Várnai C;Wingett SW;Cairns J;Collier AJ;García-Vílchez R;Furlan-Magaril M;Osborne CS;Fraser P;Rugg-Gunn PJ;Spivakov M
通讯作者：
Spivakov M
影响因子：
10.5
作者：
Denker A;de Laat W
通讯作者：
de Laat W
影响因子：
46.9
作者：
de Vree, Paula J. P.;de Wit, Elzo;de Laat, Wouter
通讯作者：
de Laat, Wouter