CTCF-organized Chromatin Structures Mediate the Spatio-temporal Propagation of Replication Foci

by Qian Peter Su*, Ziqing Winston Zhao*, Luming Meng, Miao Ding, Weiwei Zhang, Yongzheng Li, Mengzhu Liu, Rongqin Li, Yi-Qin Gao, Xiaoliang Sunney Xie, Yujie Sun

bioRxiv (2019) doi: https://doi.org/10.1101/525915

Mammalian DNA replication is initiated at numerous replication origins, which are clustered into thousands of replication domains (RDs) across the genome. However, it remains unclear whether
the replication origins within each RD are activated stochastically. To understand how replication is regulated at the sub-RD level, we directly visualized the spatio-temporal organization, morphology, and in situ epigenetic signatures of individual replication foci (RFi) across S-phase using super-resolution stochastic optical reconstruction microscopy (STORM). Importantly, we revealed a hierarchical radial pattern of RFi propagation that reverses its directionality from early to late S-phase, and is diminished upon caffeine treatment or CTCF knockdown. Together with simulation and bioinformatic analyses, our findings point to a ‘CTCF-organized REplication Propagation’ (CoREP) model. The CoREP model suggests a non-random selection mechanism for replication activation mediated by CTCF at the sub-RD level, as well as the critical involvement of local chromatin environment in regulating replication in space and time.