小柯机器人

美国宾夕法尼亚大学Jennifer E. Phillips-Cremins团队发现，黏连蛋白介导的环锚定限制人类复制起源的位置。2022年6月8日，国际知名学术期刊《自然》在线发表了这一成果。

研究人员剖析了拓扑关联域（TAD）、subTAD和环在复制起始区（IZ）定位中的作用。研究人员通过指示环的角点的存在和CTCF模体的方向对TAD和subTAD进行分层。研究人员发现，高效的、早期复制的IZ定位于相邻角点TAD之间的边界，这些角点TAD由高密度的CTCF模体阵列锚定，方向不同。相比之下，低效率的IZ定位在较弱的无点边界。在G1期间取消了聚合酶介导的环状挤压后，高效率的IZ在具有复杂CTCF模体方向的边界上变得弥漫和离域。此外，G1期敲除辅酶卸载因子WAPL会导致长距离环的获得和同一边界上IZ的定位变窄。

最后，靶向删除或插入特定的边界会导致局部复制时间的改变，这与IZ的丢失或获得相一致。这些数据支持一个模型，即在基因编码的TAD和subTAD边界的黏连蛋白介导的环挤压和停滞是人类S期复制起源位置的一个重要决定因素。

据介绍，DNA复制是通过一系列错综复杂的分子事件进行的，是基因组稳定的基础。目前，人类基因组中复制起源的位置是如何确定的尚不清楚。

附：英文原文

Title: Cohesin-mediated loop anchors confine the locations of human replication origins

Author: Emerson, Daniel J., Zhao, Peiyao A., Cook, Ashley L., Barnett, R. Jordan, Klein, Kyle N., Saulebekova, Dalila, Ge, Chunmin, Zhou, Linda, Simandi, Zoltan, Minsk, Miriam K., Titus, Katelyn R., Wang, Weitao, Gong, Wanfeng, Zhang, Di, Yang, Liyan, Venev, Sergey V., Gibcus, Johan H., Yang, Hongbo, Sasaki, Takayo, Kanemaki, Masato T., Yue, Feng, Dekker, Job, Chen, Chun-Long, Gilbert, David M., Phillips-Cremins, Jennifer E.

Issue&Volume: 2022-06-08

Abstract: DNA replication occurs through an intricately regulated series of molecular events and is fundamental for genome stability1,2. 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)3,4,5,6, subTADs7 and loops8 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.

DOI: 10.1038/s41586-022-04803-0

Source: https://www.nature.com/articles/s41586-022-04803-0

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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