Multi-feature clustering of CTCF binding creates robustness for loop extrusion blocking and Topologically Associating Domain boundaries.
Multi-feature clustering of CTCF binding creates robustness for loop extrusion blocking and Topologically Associating Domain boundaries.
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DOI：
10.1038/s41467-023-41265-y
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发表时间：
2023-09-12
影响因子：
16.6
通讯作者：
Noordermeer D
中科院分区：
文献类型：
--
作者：
Chang LH;Ghosh S;Papale A;Luppino JM;Miranda M;Piras V;Degrouard J;Edouard J;Poncelet M;Lecouvreur N;Bloyer S;Leforestier A;Joyce EF;Holcman D;Noordermeer D
拓扑关联结构域（TADs）将脊椎动物基因组分隔成隔离的调控区域，这些区域集中于基因组相关过程。TADs是由内聚蛋白介导的环挤出形成的，其中许多外聚边界由CTCF绝缘子蛋白的成簇结合位点组成。在这里，我们确定CTCF结合的这种聚集如何有助于阻止环挤出和TAD之间的绝缘。我们确定了三个功能的CTCF结合在强的边界，由强烈的约束和紧密间隔的CTCF结合峰，与DNA结合图案在这些峰内的进一步富集富集。在具有正常和扰动CTCF结合的细胞中使用多接触Nano-C分析，我们确定单个CTCF结合位点有助于阻止环挤出，但以不完全的方式。当聚集时，单个CTCF结合位点因此在相邻的TAD之间产生逐步绝缘。基于这些结果，我们提出了一个模型，使多个实例的时间循环挤压阻塞TADs之间创建强大的绝缘。大多数哺乳动物的DNA边界，分离功能性染色体结构域，结合CTCF蛋白。在这里，作者确定了CTCF结合位点在细胞边界的多级聚类，并确认了它们对细胞形成的单独贡献。
Topologically Associating Domains (TADs) separate vertebrate genomes into insulated regulatory neighborhoods that focus genome-associated processes. TADs are formed by Cohesin-mediated loop extrusion, with many TAD boundaries consisting of clustered binding sites of the CTCF insulator protein. Here we determine how this clustering of CTCF binding contributes to the blocking of loop extrusion and the insulation between TADs. We identify enrichment of three features of CTCF binding at strong TAD boundaries, consisting of strongly bound and closely spaced CTCF binding peaks, with a further enrichment of DNA-binding motifs within these peaks. Using multi-contact Nano-C analysis in cells with normal and perturbed CTCF binding, we establish that individual CTCF binding sites contribute to the blocking of loop extrusion, but in an incomplete manner. When clustered, individual CTCF binding sites thus create a stepwise insulation between neighboring TADs. Based on these results, we propose a model whereby multiple instances of temporal loop extrusion blocking create strong insulation between TADs. Most mammalian TAD boundaries, which separate functional chromosomal domains, bind the CTCF protein. Here, the authors identify multi-level clustering of CTCF binding sites at TAD boundaries and confirm their individual contribution to TAD formation.
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DOI：
10.1126/science.abn6583
发表时间：
2022-04-29
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.5
作者：
Dowen JM;Fan ZP;Hnisz D;Ren G;Abraham BJ;Zhang LN;Weintraub AS;Schujiers J;Lee TI;Zhao K;Young RA
通讯作者：
Young RA
影响因子：
5.9
作者：
Dowen, Jill M.;Bilodeau, Steve;Young, Richard A.
通讯作者：
Young, Richard A.
影响因子：
30.8
作者：
Allahyar, Amin;Vermeulen, Carlo;de Laat, Wouter
通讯作者：
de Laat, Wouter
影响因子：
30.8
作者：
Chakraborty, Shreeta;Kopitchinski, Nina;Rocha, Pedro P.
通讯作者：
Rocha, Pedro P.