小柯机器人

奥地利科学院分子生物技术研究所Kikuë Tachibana、美国麻省理工学院Leonid A. Mirny和德国马克斯普朗克生物化学研究所Karl E. Duderstadt研究团队发现，微染色体维持(MCM)复合物是限制cohesin介导环挤压的屏障。这一研究成果于2022年5月18日发表在国际学术期刊《自然》上。

研究人员发现MCM复合物是限制G1期环挤出的屏障。小鼠受精卵的单核Hi-C（高分辨率染色体构象捕获）表明，MCM负载减少了CTCF锚定环并降低了拓扑关联域(TAD)边界，这表明在达到CTCF之前环挤压受到阻碍。这种效应在HCT116细胞中也存在，其中MCM影响CTCF锚定环的数量和基因表达。模拟实验表明，MCM是大量存在的、随机定位和部分可渗透的屏障。单分子成像表明，体外MCM是限制黏连蛋白易位的重要物理屏障。

值得注意的是，含有人MCM3 Cohesin相互作用基序的嵌合酵母MCM会诱导cohesin暂停，这表明MCM是具有结合位点的“活性”屏障。这些发现揭示了cohesin可以通过环挤压到达MCM的可能，这决定了姐妹染色单体凝聚的基因组位点。基于体内、计算机和体外数据，该研究表明不同的环挤压屏障塑造了三维基因组。

研究人员表示，真核基因组被压缩成环和TAD，这有助于转录、重组和基因组稳定性。Cohesin将DNA挤出成环，这些环会延长，直到遇到CTCF边界。关于循环挤压是否受到DNA结合动力学的阻碍知之甚少。

附：英文原文

Title: MCM complexes are barriers that restrict cohesin-mediated loop extrusion

Author: Dequeker, Bart J. H., Scherr, Matthias J., Brando, Hugo B., Gassler, Johanna, Powell, Sean, Gaspar, Imre, Flyamer, Ilya M., Lalic, Aleksandar, Tang, Wen, Stocsits, Roman, Davidson, Iain F., Peters, Jan-Michael, Duderstadt, Karl E., Mirny, Leonid A., Tachibana, Kiku

Issue&Volume: 2022-05-18

Abstract: Eukaryotic genomes are compacted into loops and topologically associating domains (TADs)1,2,3, which contribute to transcription, recombination and genomic stability4,5. Cohesin extrudes DNA into loops that are thought to lengthen until CTCF boundaries are encountered6,7,8,9,10,11,12. 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.

DOI: 10.1038/s41586-022-04730-0

Source: https://www.nature.com/articles/s41586-022-04730-0

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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