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

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 the mouse genome. Surprisingly, enzymatic rates can vary as much as two orders of magnitude between CpGs with identical steady-state measurements. 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 the first genome-scale map of methylation kinetics, revealing highly variable and context specific activity for the DNA methylation machinery. Overall design: Analysis of DNA methylation dynamics in mouse embryonic stem cells