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

Cell Res. 2020 Nov;30(11):980-996. doi: 10.1038/s41422-020-0359-9. Epub 2020 Jun 24.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics*
  • Animals
  • CCAAT-Enhancer-Binding Proteins / chemistry
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Carcinogenesis / pathology
  • CpG Islands / genetics
  • DNA (Cytosine-5-)-Methyltransferase 1 / metabolism
  • DNA Methylation / genetics*
  • DNA Replication / genetics
  • Genome, Human
  • HeLa Cells
  • Histones / metabolism
  • Humans
  • Inheritance Patterns / genetics*
  • Kinetics
  • Lysine / metabolism
  • Mice
  • Mitosis / genetics*
  • Mouse Embryonic Stem Cells / metabolism
  • Nucleosomes / metabolism
  • Proliferating Cell Nuclear Antigen / metabolism
  • Protein Binding
  • Protein Domains
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / metabolism


  • CCAAT-Enhancer-Binding Proteins
  • Histones
  • Nucleosomes
  • Proliferating Cell Nuclear Antigen
  • DNA (Cytosine-5-)-Methyltransferase 1
  • UHRF1 protein, human
  • Ubiquitin-Protein Ligases
  • Lysine