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

摘要

Mitotic inheritance of the DNA methylome is a challenging task for the maintenance of cell identity.Whether DNA methylation pattem in different genomic contexts can all be faithfully maintained is an open question.A repiication-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 varlous 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.