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

Author

Listed:
  • Paul Adrian Ginno

    (Friedrich Miescher Institute for Biomedical Research)

  • Dimos Gaidatzis

    (Friedrich Miescher Institute for Biomedical Research
    Swiss Institute of Bioinformatics)

  • Angelika Feldmann

    (Friedrich Miescher Institute for Biomedical Research
    Department of Biochemistry, University of Oxford)

  • Leslie Hoerner

    (Friedrich Miescher Institute for Biomedical Research)

  • Dilek Imanci

    (Friedrich Miescher Institute for Biomedical Research
    Novartis Institutes for Biomedical Research)

  • Lukas Burger

    (Friedrich Miescher Institute for Biomedical Research
    Swiss Institute of Bioinformatics)

  • Frederic Zilbermann

    (Friedrich Miescher Institute for Biomedical Research)

  • Antoine H. F. M. Peters

    (Friedrich Miescher Institute for Biomedical Research
    University of Basel)

  • 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
    EMBL Heidelberg)

  • Dirk Schübeler

    (Friedrich Miescher Institute for Biomedical Research
    University of Basel)

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.

Suggested Citation

  • 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 & Arna, 2020. "A genome-scale map of DNA methylation turnover identifies site-specific dependencies of DNMT and TET activity," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16354-x
    DOI: 10.1038/s41467-020-16354-x
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    Cited by:

    1. Simon D. Schwarz & Jianming Xu & Kapila Gunasekera & David Schürmann & Cathrine B. Vågbø & Elena Ferrari & Geir Slupphaug & Michael O. Hottiger & Primo Schär & Roland Steinacher, 2024. "Covalent PARylation of DNA base excision repair proteins regulates DNA demethylation," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Kosuke Yamaguchi & Xiaoying Chen & Brianna Rodgers & Fumihito Miura & Pavel Bashtrykov & Frédéric Bonhomme & Catalina Salinas-Luypaert & Deis Haxholli & Nicole Gutekunst & Bihter Özdemir Aygenli & Lau, 2024. "Non-canonical functions of UHRF1 maintain DNA methylation homeostasis in cancer cells," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Andrea Lauria & Guohua Meng & Valentina Proserpio & Stefania Rapelli & Mara Maldotti & Isabelle Laurence Polignano & Francesca Anselmi & Danny Incarnato & Anna Krepelova & Daniela Donna & Chiara Levra, 2023. "DNMT3B supports meso-endoderm differentiation from mouse embryonic stem cells," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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