Volume 30, No 11, Nov 2020

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 30 Issue 11, November 2020: 980-996

ORIGINAL ARTICLES

Kinetics and mechanisms of mitotic inheritance of DNA methylation and their roles in aging-associated methylome deterioration

Xuan Ming^1,2,3 , Zhuqiang Zhang² , Zhuoning Zou⁴ , Cong Lv⁵ , Qiang Dong² , Qixiang He⁴ , Yangyang Yi^2,4 , Yingfeng Li² , Hailin Wang⁵ , Bing Zhu^2,4,*

¹Graduate Program, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
²National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
³National Institute of Biological Sciences, Beijing 102206, China
⁴College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
⁵State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
^†These authors contributed equally: Xuan Ming, Zhuqiang Zhang
Correspondence: Bing Zhu(zhubing@ibp.ac.cn)

Mitotic inheritance of the DNA methylome is a challenging task for the maintenance of cell identity. Whether DNA methylation pattern in different genomic contexts can all be faithfully maintained is an open question. A replication-coupled DNA methylation maintenance model was proposed decades ago, but some observations suggest that a replication-uncoupled maintenance mechanism exists. However, the capacity and the underlying molecular events of replication-uncoupled maintenance are unclear. By measuring maintenance kinetics at the single-molecule level and assessing mutant cells with perturbation of various mechanisms, we found that the kinetics of replication-coupled maintenance are governed by the UHRF1–Ligase 1 and PCNA–DNMT1 interactions, whereas nucleosome occupancy and the interaction between UHRF1 and methylated H3K9 specifically regulate replication-uncoupled maintenance. Surprisingly, replication-uncoupled maintenance is sufficiently robust to largely restore the methylome when replication-coupled maintenance is severely impaired. However, solo-WCGW sites and other CpG sites displaying aging- and cancer-associated hypomethylation exhibit low maintenance efficiency, suggesting that although quite robust, mitotic inheritance of methylation is imperfect and that this imperfection may contribute to selective hypomethylation during aging and tumorigenesis.

https://doi.org/10.1038/s41422-020-0359-9

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