@article{ee3bb1d07be9400cb659ba05b644d93b,
title = "Cohesin-mediated loop anchors confine the locations of human replication origins",
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.",
author = "Emerson, {Daniel J.} and Zhao, {Peiyao A.} and Cook, {Ashley L.} and Barnett, {R. Jordan} and Klein, {Kyle N.} and Dalila Saulebekova and Chunmin Ge and Linda Zhou and Zoltan Simandi and Minsk, {Miriam K.} and Titus, {Katelyn R.} and Weitao Wang and Wanfeng Gong and Di Zhang and Liyan Yang and Venev, {Sergey V.} and Gibcus, {Johan H.} and Hongbo Yang and Takayo Sasaki and Kanemaki, {Masato T.} and Feng Yue and Job Dekker and Chen, {Chun Long} and Gilbert, {David M.} and Phillips-Cremins, {Jennifer E.}",
note = "Funding Information: We thank members of the 4D Nucleome community and the laboratories of J.E.P.-C. and D.M.G. for helpful discussions. J.E.P.-C. is a New York Stem Cell Foundation – Robertson Investigator and an Alfred P. Sloan Foundation Fellow. J.D. is an investigator of the Howard Hughes Medical Institute. This research was supported by National Institute of Mental Health grants (1R011MH120269 and 1DP1MH129957; J.E.P.-C.), 4D Nucleome Common Fund grants (1U01HL12999801, 1U01DK127405 and 1U01DA052715; J.E.P.-C.), a National Science Foundation (NSF) CAREER Award (CBE-1943945; J.E.P.-C.), an NSF Emerging Frontiers in Research Innovation grant (1933400; J.E.P.-C.), 4D Nucleome Common Fund grants (DK107980 and HG011536; J.D.) and National Institutes of Health grants (R01HG010658 and U54DK107965; D.M.G.). The PhD fellowship to D.S. was provided by the CNRS 80|Prime interdisciplinary programme and W.W. was supported by a COFUND IC-3i International PhD fellowship. Funding Information: We thank members of the 4D Nucleome community and the laboratories of J.E.P.-C. and D.M.G. for helpful discussions. J.E.P.-C. is a New York Stem Cell Foundation – Robertson Investigator and an Alfred P. Sloan Foundation Fellow. J.D. is an investigator of the Howard Hughes Medical Institute. This research was supported by National Institute of Mental Health grants (1R011MH120269 and 1DP1MH129957; J.E.P.-C.), 4D Nucleome Common Fund grants (1U01HL12999801, 1U01DK127405 and 1U01DA052715; J.E.P.-C.), a National Science Foundation (NSF) CAREER Award (CBE-1943945; J.E.P.-C.), an NSF Emerging Frontiers in Research Innovation grant (1933400; J.E.P.-C.), 4D Nucleome Common Fund grants (DK107980 and HG011536; J.D.) and National Institutes of Health grants (R01HG010658 and U54DK107965; D.M.G.). The PhD fellowship to D.S. was provided by the CNRS 80|Prime interdisciplinary programme and W.W. was supported by a COFUND IC-3i International PhD fellowship. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = jun,
day = "23",
doi = "10.1038/s41586-022-04803-0",
language = "English (US)",
volume = "606",
pages = "812--819",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Research",
number = "7915",
}