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

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
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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)3-6, 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.

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Emerson DJ, Zhao PA, Cook AL, Barnett RJ, Klein KN, Saulebekova D, Ge C, Zhou L, Simandi Z, Minsk MK, Titus KR, Wang W, Gong W, Zhang D, Yang L, Venev SV, Gibcus JH, Yang H, Sasaki T, Kanemaki MT, Yue F, Dekker J, Chen CL, Gilbert DM, Phillips-Cremins JE. Cohesin-mediated loop anchors confine the locations of human replication origins. Nature. 2022 Jun;606(7915):812-819. doi: 10.1038/s41586-022-04803-0. Epub 2022 Jun 8. PMID: 35676475; PMCID: PMC9217744.

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10.1038/s41586-022-04803-0
PubMed ID
35676475
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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2022Attribution 4.0 International