Transcription-coupled structural dynamics of topologically associating domains regulate replication origin efficiency

Genome Biology

Yanyan Jin¹  Haizhen Long²  Liwei Zhang²  Guohong Li³  Yingping Hou⁴  Yuan Cao⁵  Mengling Zhang⁵  Xiaodong Guan⁵  Yao Wang⁵  Yizhi Qin⁵  Yongzheng Li⁶  Boxin Xue⁷  Yujie Sun⁸  Qian Peter Su⁹ 

[1] Department of Neurobiology, Beijing Centre of Neural Regeneration and Repair, Capital Medical University, 100101, Beijing, China;National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China;National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China;University of Chinese Academy of Sciences, 100049, Beijing, China;Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, 100871, Beijing, China;State Key Laboratory of Membrane Biology, Biomedical Pioneer Innovation Center (BIOPIC), School of Life Sciences, Peking University, 100871, Beijing, China;State Key Laboratory of Membrane Biology, Biomedical Pioneer Innovation Center (BIOPIC), School of Life Sciences, Peking University, 100871, Beijing, China;Academy for Advanced Interdisciplinary Studies, Peking University, 100871, Beijing, China;State Key Laboratory of Membrane Biology, Biomedical Pioneer Innovation Center (BIOPIC), School of Life Sciences, Peking University, 100871, Beijing, China;College of Chemistry and Molecular Engineering, Peking University, 100871, Beijing, China;State Key Laboratory of Membrane Biology, Biomedical Pioneer Innovation Center (BIOPIC), School of Life Sciences, Peking University, 100871, Beijing, China;College of Future Technology, Peking University, 100871, Beijing, China;State Key Laboratory of Membrane Biology, Biomedical Pioneer Innovation Center (BIOPIC), School of Life Sciences, Peking University, 100871, Beijing, China;School of Biomedical Engineering, Faculty of Engineering and Information Technology, University of Technology Sydney, 2007, Sydney, NSW, Australia;

关键词: Replication origin;    Topologically associating domain (TAD);    Chromatin structure;    Transcription;    Super-resolution imaging;    STORM;   

DOI  :  10.1186/s13059-021-02424-w

来源: Springer

【 摘 要 】

BackgroundMetazoan cells only utilize a small subset of the potential DNA replication origins to duplicate the whole genome in each cell cycle. Origin choice is linked to cell growth, differentiation, and replication stress. Although various genetic and epigenetic signatures have been linked to the replication efficiency of origins, there is no consensus on how the selection of origins is determined.ResultsWe apply dual-color stochastic optical reconstruction microscopy (STORM) super-resolution imaging to map the spatial distribution of origins within individual topologically associating domains (TADs). We find that multiple replication origins initiate separately at the spatial boundary of a TAD at the beginning of the S phase. Intriguingly, while both high-efficiency and low-efficiency origins are distributed homogeneously in the TAD during the G1 phase, high-efficiency origins relocate to the TAD periphery before the S phase. Origin relocalization is dependent on both transcription and CTCF-mediated chromatin structure. Further, we observe that the replication machinery protein PCNA forms immobile clusters around TADs at the G1/S transition, explaining why origins at the TAD periphery are preferentially fired.ConclusionOur work reveals a new origin selection mechanism that the replication efficiency of origins is determined by their physical distribution in the chromatin domain, which undergoes a transcription-dependent structural re-organization process. Our model explains the complex links between replication origin efficiency and many genetic and epigenetic signatures that mark active transcription. The coordination between DNA replication, transcription, and chromatin organization inside individual TADs also provides new insights into the biological functions of sub-domain chromatin structural dynamics.

【 授权许可】

CC BY