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

作　　者：Xuan Ming Zhuqiang Zhang Zhuoning Zou Cong Lv Qiang Dong Qixiang He Yangyang Yi Yingfeng Li Hailin Wang Bing Zhu 

机构地区：[1]Graduate Program,Peking Union Medical College and Chinese Academy of Medical Sciences,Beijing,100730,China [2]National Laboratory of Biomacromolecules,CAS Center for Excellence in Biomacromolecules,Institute of Biophysics,Chinese Academy of Sciences,Beijing,100101,China [3]National Institute of Biological Sciences,Beijing,102206,China [4]College of Life Sciences,University of Chinese Academy of Sciences,Beijing,100049,China [5]State Key Laboratory of Environmental Chemistry and Ecotoxicology,Research Center for Eco-Environmental Sciences,Chinese Academy of Sciences,Beijing,100085,China

出　　处：《Cell Research》2020年第11期980-996,共17页细胞研究（英文版）

基　　金：This work was primarily supported by the National Natural Science Foundation of China(31530047);This work was also supported by the Ministry of Science and Technology of China(2016YFA0100400);the Chinese Academy of Sciences(XDB39000000 and QYZDYSSW-SMC031);Z.Z.is sponsored by the Youth Innovation Promotion Association(2017133)of the Chinese Academy of Sciences.

摘　　要：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.

关 键 词：IMPAIRED aging kinetics 

分 类 号：Q253[生物学—细胞生物学]