Analysis of sub-kilobase chromatin topology reveals nano-scale regulatory interactions with variable dependence on cohesin and CTCF.
Analysis of sub-kilobase chromatin topology reveals nano-scale regulatory interactions with variable dependence on cohesin and CTCF.
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DOI：
10.1038/s41467-022-29696-5
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发表时间：
2022-04-19
影响因子：
16.6
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中科院分区：
文献类型：
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增强子和启动子主要在大规模拓扑关联结构域（TADs）内相互作用，所述大规模拓扑关联结构域通过由粘附素和CTCF介导的环挤出形成。然而，目前还不清楚复杂的染色质结构是否存在于亚染色酶规模，以及在何种程度上精细规模的调控相互作用依赖于环挤出。为了解决这些问题，我们提出了一种基于MNase的染色体构象捕获（3C）方法，该方法使我们能够生成迄今为止最详细的局部相互作用数据（20 bp分辨率），并精确地研究粘连蛋白和CTCF耗尽对染色质结构的影响。我们的数据显示，顺式调控元件具有独特的内部纳米级结构，其中局部绝缘依赖于CTCF，但独立于粘附素。与此相反，我们发现，耗尽的凝聚素导致一个微妙的减少，在较长范围的增强子-启动子相互作用和CTCF耗尽可能会导致重新布线的监管接触。总之，我们的数据表明，环挤出不是必不可少的增强子-启动子相互作用，但有助于其鲁棒性和特异性，并精确调控基因表达。染色体构象捕获（3C）技术已经捕获了大规模的3D基因组结构.在这里，作者提出了他们的“Tiled-MCC”方法，用于以非常高的分辨率（高达20 bp）生成跨兆碱基规模基因座的3C数据，这使他们能够观察纳米级染色质结构，并研究这些结构如何依赖于粘附素和CTCF。
Enhancers and promoters predominantly interact within large-scale topologically associating domains (TADs), which are formed by loop extrusion mediated by cohesin and CTCF. However, it is unclear whether complex chromatin structures exist at sub-kilobase-scale and to what extent fine-scale regulatory interactions depend on loop extrusion. To address these questions, we present an MNase-based chromosome conformation capture (3C) approach, which has enabled us to generate the most detailed local interaction data to date (20 bp resolution) and precisely investigate the effects of cohesin and CTCF depletion on chromatin architecture. Our data reveal that cis-regulatory elements have distinct internal nano-scale structures, within which local insulation is dependent on CTCF, but which are independent of cohesin. In contrast, we find that depletion of cohesin causes a subtle reduction in longer-range enhancer-promoter interactions and that CTCF depletion can cause rewiring of regulatory contacts. Together, our data show that loop extrusion is not essential for enhancer-promoter interactions, but contributes to their robustness and specificity and to precise regulation of gene expression. Chromosome conformation capture (3 C) techniques have captured largescale 3D genome architecture. Here the authors present their “Tiled-MCC” approach for generation of 3 C data across megabase-scale loci at very high (up to 20 bp) resolution, which allowed them to observe nano-scale chromatin structures and investigate how these structures depend on cohesin and CTCF.
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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：
48
作者：
Hsieh, Tsung-Han S.;Fudenberg, Geoffrey;Rando, Oliver J.
通讯作者：
Rando, Oliver J.
影响因子：
7
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Dryden NH;Broome LR;Dudbridge F;Johnson N;Orr N;Schoenfelder S;Nagano T;Andrews S;Wingett S;Kozarewa I;Assiotis I;Fenwick K;Maguire SL;Campbell J;Natrajan R;Lambros M;Perrakis E;Ashworth A;Fraser P;Fletcher O
通讯作者：
Fletcher O
影响因子：
30.5
作者：
Cuartero S;Weiss FD;Dharmalingam G;Guo Y;Ing-Simmons E;Masella S;Robles-Rebollo I;Xiao X;Wang YF;Barozzi I;Djeghloul D;Amano MT;Niskanen H;Petretto E;Dowell RD;Tachibana K;Kaikkonen MU;Nasmyth KA;Lenhard B;Natoli G;Fisher AG;Merkenschlager M
通讯作者：
Merkenschlager M
影响因子：
8.8
作者：
Blinka S;Reimer MH Jr;Pulakanti K;Rao S
通讯作者：
Rao S