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

Paul Adrian Ginno, Dimos Gaidatzis, Angelika Feldmann, Leslie Hoerner, Dilek Imanci, Lukas Burger, Frederic Zilbermann, Antoine H. F. M. Peters, Frank Edenhofer, Sébastien A. Smallwood, Arnaud R. Krebs and Dirk Schübeler ()
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Paul Adrian Ginno: Friedrich Miescher Institute for Biomedical Research
Dimos Gaidatzis: Friedrich Miescher Institute for Biomedical Research
Angelika Feldmann: Friedrich Miescher Institute for Biomedical Research
Leslie Hoerner: Friedrich Miescher Institute for Biomedical Research
Dilek Imanci: Friedrich Miescher Institute for Biomedical Research
Lukas Burger: Friedrich Miescher Institute for Biomedical Research
Frederic Zilbermann: Friedrich Miescher Institute for Biomedical Research
Antoine H. F. M. Peters: Friedrich Miescher Institute for Biomedical Research
Frank Edenhofer: Leopold-Franzens-University Innsbruck & CMBI
Sébastien A. Smallwood: Friedrich Miescher Institute for Biomedical Research
Arnaud R. Krebs: Friedrich Miescher Institute for Biomedical Research
Dirk Schübeler: Friedrich Miescher Institute for Biomedical Research

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-16354-x

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