Cohesin-mediated loop anchors confine the locations of human replication origins.
Cohesin-mediated loop anchors confine the locations of human replication origins.
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DOI：
10.1038/s41586-022-04803-0
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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：
DNA复制通过一系列复杂调控的分子事件发生，是基因组稳定性的基础。目前，还不清楚复制起点在人类基因组中的位置如何确定。在这里，我们解剖的拓扑关联域（TADs），subTADs和循环中的定位复制起始区（IZs）的作用。我们分层的TADs和subTADs的存在下，角点指示循环和CTCF图案的方向。我们发现，高效率，早期复制IZs本地化到相邻的角点TADs锚定的高密度阵列的发散和收敛取向的CTCF图案之间的边界。相比之下，低效率的IZs本地化到较弱的无点边界。在G1期内，在消融了粘附素介导的环挤出之后，高效IZ在具有复杂CTCF基序取向的边界处变得弥散和离域。此外，G1敲低的内聚素卸载因子WAPL的结果在获得的长程循环和缩小的本地化的IZs在相同的边界。最后，特定边界的靶向缺失或插入分别导致与IZ损失或增益一致的局部复制时间偏移。我们的数据支持一个模型，其中粘附素介导的环挤出和停滞在一个子集的遗传编码的DNA和subDNA的边界是一个重要的决定因素的复制起点在人类S期的位置。一项研究表明，人类基因组的三维构象影响DNA复制起始区的定位，突出了粘着蛋白介导的环锚作为其精确位置的重要决定因素。
DNA replication occurs through an intricately regulated series of molecular events and is fundamental for genome stability. At present, it is unknown how the locations of replication origins are determined in the human genome. Here we dissect the role of topologically associating domains (TADs), subTADs and loops in the positioning of replication initiation zones (IZs). We stratify TADs and subTADs by the presence of corner-dots indicative of loops and the orientation of CTCF motifs. We find that high-efficiency, early replicating IZs localize to boundaries between adjacent corner-dot TADs anchored by high-density arrays of divergently and convergently oriented CTCF motifs. By contrast, low-efficiency IZs localize to weaker dotless boundaries. Following ablation of cohesin-mediated loop extrusion during G1, high-efficiency IZs become diffuse and delocalized at boundaries with complex CTCF motif orientations. Moreover, G1 knockdown of the cohesin unloading factor WAPL results in gained long-range loops and narrowed localization of IZs at the same boundaries. Finally, targeted deletion or insertion of specific boundaries causes local replication timing shifts consistent with IZ loss or gain, respectively. Our data support a model in which cohesin-mediated loop extrusion and stalling at a subset of genetically encoded TAD and subTAD boundaries is an essential determinant of the locations of replication origins in human S phase. A study shows that the three-dimensional conformation of the human genome influences the positioning of DNA replication initiation zones, highlighting cohesin-mediated loop anchors as essential determinants of their precise location.
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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：
48
作者：
Norton HK;Emerson DJ;Huang H;Kim J;Titus KR;Gu S;Bassett DS;Phillips-Cremins JE
通讯作者：
Phillips-Cremins JE
转录塑造 DNA 复制起始以保持基因组完整性
影响因子：
12.3
作者：
Liu Y;Ai C;Gan T;Wu J;Jiang Y;Liu X;Lu R;Gao N;Li Q;Ji X;Hu J
通讯作者：
Hu J
影响因子：
16
作者：
Hou, Chunhui;Li, Li;Qin, Zhaohui S.;Corces, Victor G.
通讯作者：
Corces, Victor G.
影响因子：
16.8
作者：
Besnard, Emilie;Babied, Amelie;Lemaitre, Jean-Marc
通讯作者：
Lemaitre, Jean-Marc