Journal Article

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

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

2022

Overview

DNA replication occurs through an intricately regulated series of molecular events and is fundamental for genome stability 1 , 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 , subTADs 7 and loops 8 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. A study shows that the three-dimensional conformation of the human genome influences the positioning of DNA replication initiation zones, highlighting cohesin-mediated loop anchors as essential determinants of their precise location.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 45 / 631/208/176 / 631/208/177 / 631/337/100/101 / 631/337/151/2352 / Ablation / Binding sites / Biochemistry, Molecular Biology / Boundaries / Cell Cycle Proteins - metabolism / Cellular Biology / Chromatin - genetics / Chromosomal Proteins, Non-Histone - metabolism / Cohesin / Cohesins / Cohesion / DNA biosynthesis / DNA Replication / Efficiency / Extrusion / Gene deletion / Genetic code / Genetics / Genomes / Genomics / Human genetics / Humanities and Social Sciences / Humans / Insertion / Life Sciences / Localization / Molecular biology / multidisciplinary / Origins / Replication / Replication Origin - genetics / Replication origins / S Phase / Science / Science (multidisciplinary) / Stalling / Subcellular Processes / Unloading