MCM complexes are barriers that restrict cohesin-mediated loop extrusion.
MCM complexes are barriers that restrict cohesin-mediated loop extrusion.
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DOI：
10.1038/s41586-022-04730-0
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发表时间：
2022-06
期刊：
影响因子：
64.8
通讯作者：
中科院分区：
文献类型：
--
作者：
真核生物基因组被压缩成环和拓扑关联结构域（TADs），其有助于转录、重组和基因组稳定性。黏连蛋白将DNA挤压成环，这些环被认为会延长，直到遇到CTCF边界。关于DNA结合机器是否阻碍了环挤出，人们知之甚少。在这里，我们表明，微型染色体维护（MCM）复杂的是一个障碍，限制环挤出在G1期。小鼠受精卵的单核Hi-C（高分辨率染色体构象捕获）显示，MCM加载减少了CTCF锚定的环，并降低了细胞边界绝缘，这表明环挤出在到达CTCF之前受到阻碍。这种效应延伸到HCT 116细胞，其中MCM影响CTCF锚定环的数量和基因表达。模拟表明，MCMs是丰富的，随机定位和部分可渗透的障碍。单分子成像显示，MCMs是一种物理屏障，在体外经常限制粘附素易位。值得注意的是，含有来自人MCM 3的粘附素相互作用基序的嵌合酵母MCMs诱导粘附素暂停，表明MCMs是具有结合位点的“活性”屏障。这些发现提高了粘附素可以通过环挤出到达MCMs的可能性，MCMs决定了建立姐妹染色单体粘附的基因组位点。在体内，在硅片和体外数据的基础上，我们得出结论，不同的环挤压障碍形状的三维基因组。胚胎的单核Hi-C、聚合物模拟和单分子成像共同揭示了MCM复合物通过阻碍DNA环挤出来影响基因组折叠和基因表达。
Eukaryotic genomes are compacted into loops and topologically associating domains (TADs), which contribute to transcription, recombination and genomic stability. Cohesin extrudes DNA into loops that are thought to lengthen until CTCF boundaries are encountered. Little is known about whether loop extrusion is impeded by DNA-bound machines. Here we show that the minichromosome maintenance (MCM) complex is a barrier that restricts loop extrusion in G1 phase. Single-nucleus Hi-C (high-resolution chromosome conformation capture) of mouse zygotes reveals that MCM loading reduces CTCF-anchored loops and decreases TAD boundary insulation, which suggests that loop extrusion is impeded before reaching CTCF. This effect extends to HCT116 cells, in which MCMs affect the number of CTCF-anchored loops and gene expression. Simulations suggest that MCMs are abundant, randomly positioned and partially permeable barriers. Single-molecule imaging shows that MCMs are physical barriers that frequently constrain cohesin translocation in vitro. Notably, chimeric yeast MCMs that contain a cohesin-interaction motif from human MCM3 induce cohesin pausing, indicating that MCMs are ‘active’ barriers with binding sites. These findings raise the possibility that cohesin can arrive by loop extrusion at MCMs, which determine the genomic sites at which sister chromatid cohesion is established. On the basis of in vivo, in silico and in vitro data, we conclude that distinct loop extrusion barriers shape the three-dimensional genome. Single-nucleus Hi-C of embryos, polymer simulations and single-molecule imaging collectively reveal that MCM complexes influence genome folding and gene expression by impeding DNA loop extrusion.
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DOI：
10.1155/2014/574850
发表时间：
2014
期刊：
Molecular biology international
影响因子：
--
作者：
Das M;Singh S;Pradhan S;Narayan G
通讯作者：
Narayan G
影响因子：
64.5
作者：
Bauer BW;Davidson IF;Canena D;Wutz G;Tang W;Litos G;Horn S;Hinterdorfer P;Peters JM
通讯作者：
Peters JM
影响因子：
3.4
作者：
Aitken, Colin Echeverria;Marshall, R. Andrew;Puglisi, Joseph D.
通讯作者：
Puglisi, Joseph D.
DOI：
10.1073/pnas.0911500106
发表时间：
2009-12-01
影响因子：
11.1
作者：
Evrin, Cecile;Clarke, Pippa;Speck, Christian
通讯作者：
Speck, Christian
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