Journal
NATURE CELL BIOLOGY
Volume 18, Issue 2, Pages 225-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb3296
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Funding
- MRC [MC_US_A652_5PY70]
- EpigeneSys network
- Marie Curie Incoming-European Fellowship
- Marie Curie Intra-European Fellowship
- MRC [MC_U120092689, G0901046] Funding Source: UKRI
- Grants-in-Aid for Scientific Research [25112001, 15K21737, 14J04310, 23249015, 25112010] Funding Source: KAKEN
- Medical Research Council [MC_U120092689, G0901046] Funding Source: researchfish
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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.
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