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

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)812-819
Number of pages8
JournalNature
Volume606
Issue number7915
DOIs
StatePublished - Jun 23 2022

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Cohesin-mediated loop anchors confine the locations of human replication origins'. Together they form a unique fingerprint.

Cite this