De novo DNA methylation drives 5hmC accumulation in mouse zygotes

Rachel Amouroux, Buhe Nashun, Kenjiro Shirane, Shoma Nakagawa, Peter W.S. Hill, Zelpha D'Souza, Manabu Nakayama, Masashi Matsuda, Aleksandra Turp, Elodie Ndjetehe, Vesela Encheva, Nobuaki R. Kudo, Haruhiko Koseki, Hiroyuki Sasaki, Petra Hajkova

    Research output: Contribution to journalArticlepeer-review

    179 Citations (Scopus)


    Zygotic epigenetic reprogramming entails genome-wide DNA demethylation that is accompanied by Tet methylcytosine dioxygenase 3 (Tet3)-driven oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC; refs 1-4). Here we demonstrate using detailed immunofluorescence analysis and ultrasensitive LC-MS-based quantitative measurements that the initial loss of paternal 5mC does not require 5hmC formation. Small-molecule inhibition of Tet3 activity, as well as genetic ablation, impedes 5hmC accumulation in zygotes without affecting the early loss of paternal 5mC. Instead, 5hmC accumulation is dependent on the activity of zygotic Dnmt3a and Dnmt1, documenting a role for Tet3-driven hydroxylation in targeting de novo methylation activities present in the early embryo. Our data thus provide further insights into the dynamics of zygotic reprogramming, revealing an intricate interplay between DNA demethylation, de novo methylation and Tet3-driven hydroxylation.

    Original languageEnglish
    Pages (from-to)225-233
    Number of pages9
    JournalNature Cell Biology
    Issue number2
    Publication statusPublished - Jan 28 2016

    All Science Journal Classification (ASJC) codes

    • Cell Biology


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