A genome-scale map of DNA methylation turnover identifies site-specific dependencies of DNMT and TET activity

Nat Commun. 2020 May 29;11(1):2680. doi: 10.1038/s41467-020-16354-x.


DNA methylation is considered a stable epigenetic mark, yet methylation patterns can vary during differentiation and in diseases such as cancer. Local levels of DNA methylation result from opposing enzymatic activities, the rates of which remain largely unknown. Here we developed a theoretical and experimental framework enabling us to infer methylation and demethylation rates at 860,404 CpGs in mouse embryonic stem cells. We find that enzymatic rates can vary as much as two orders of magnitude between CpGs with identical steady-state DNA methylation. Unexpectedly, de novo and maintenance methylation activity is reduced at transcription factor binding sites, while methylation turnover is elevated in transcribed gene bodies. Furthermore, we show that TET activity contributes substantially more than passive demethylation to establishing low methylation levels at distal enhancers. Taken together, our work unveils a genome-scale map of methylation kinetics, revealing highly variable and context-specific activity for the DNA methylation machinery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites / genetics
  • Cell Line
  • Chromosome Mapping
  • CpG Islands / genetics*
  • DNA (Cytosine-5-)-Methyltransferase 1 / genetics
  • DNA (Cytosine-5-)-Methyltransferase 1 / metabolism*
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Demethylation*
  • DNA Methylation / genetics*
  • DNA Methyltransferase 3A
  • DNA Methyltransferase 3B
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Dioxygenases / genetics
  • Dioxygenases / metabolism
  • Epigenesis, Genetic / genetics
  • Genome / genetics
  • Histones / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mouse Embryonic Stem Cells / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Regulatory Sequences, Nucleic Acid / genetics
  • Transcription Factors / metabolism
  • Transcription, Genetic / genetics


  • DNA-Binding Proteins
  • Histones
  • Proto-Oncogene Proteins
  • TET1 protein, mouse
  • Transcription Factors
  • Dioxygenases
  • Tet2 protein, mouse
  • Tet3 protein, mouse
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA Methyltransferase 3A
  • Dnmt1 protein, mouse