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. Kanemaki, Feng Yue, Job Dekker, Chun-Long Chen, David M. Gilbert and Jennifer E. Phillips-Cremins ()
Additional contact information
Daniel J. Emerson: University of Pennsylvania
Peiyao A. Zhao: Florida State University
Ashley L. Cook: University of Pennsylvania
R. Jordan Barnett: University of Pennsylvania
Kyle N. Klein: Florida State University
Dalila Saulebekova: Institut Curie, PSL Research University, CNRS UMR3244, Dynamics of Genetic Information, Sorbonne Université
Chunmin Ge: University of Pennsylvania
Linda Zhou: University of Pennsylvania
Zoltan Simandi: University of Pennsylvania
Miriam K. Minsk: University of Pennsylvania
Katelyn R. Titus: University of Pennsylvania
Weitao Wang: Institut Curie, PSL Research University, CNRS UMR3244, Dynamics of Genetic Information, Sorbonne Université
Wanfeng Gong: University of Pennsylvania
Di Zhang: Children’s Hospital of Pennsylvania
Liyan Yang: University of Massachusetts Chan Medical School
Sergey V. Venev: University of Massachusetts Chan Medical School
Johan H. Gibcus: University of Massachusetts Chan Medical School
Hongbo Yang: Northwestern University
Takayo Sasaki: San Diego Biomedical Research Institute
Masato T. Kanemaki: Research Organization of Information and Systems (ROIS)
Feng Yue: Northwestern University
Job Dekker: University of Massachusetts Chan Medical School
Chun-Long Chen: Institut Curie, PSL Research University, CNRS UMR3244, Dynamics of Genetic Information, Sorbonne Université
David M. Gilbert: Florida State University
Jennifer E. Phillips-Cremins: University of Pennsylvania

Nature, 2022, vol. 606, issue 7915, 812-819

Abstract: 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.

Date: 2022
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41586-022-04803-0 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:606:y:2022:i:7915:d:10.1038_s41586-022-04803-0

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-022-04803-0

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().