DNA methyltransferases 3A and 3B target specific sequences during mouse gastrulation.
Journal
Nature structural & molecular biology
ISSN: 1545-9985
Titre abrégé: Nat Struct Mol Biol
Pays: United States
ID NLM: 101186374
Informations de publication
Date de publication:
12 2022
12 2022
Historique:
received:
23
08
2021
accepted:
02
11
2022
pubmed:
13
12
2022
medline:
21
12
2022
entrez:
12
12
2022
Statut:
ppublish
Résumé
In mammalian embryos, DNA methylation is initialized to maximum levels in the epiblast by the de novo DNA methyltransferases DNMT3A and DNMT3B before gastrulation diversifies it across regulatory regions. Here we show that DNMT3A and DNMT3B are differentially regulated during endoderm and mesoderm bifurcation and study the implications in vivo and in meso-endoderm embryoid bodies. Loss of both Dnmt3a and Dnmt3b impairs exit from the epiblast state. More subtly, independent loss of Dnmt3a or Dnmt3b leads to small biases in mesoderm-endoderm bifurcation and transcriptional deregulation. Epigenetically, DNMT3A and DNMT3B drive distinct methylation kinetics in the epiblast, as can be predicted from their strand-specific sequence preferences. The enzymes compensate for each other in the epiblast, but can later facilitate lineage-specific methylation kinetics as their expression diverges. Single-cell analysis shows that differential activity of DNMT3A and DNMT3B combines with replication-linked methylation turnover to increase epigenetic plasticity in gastrulation. Together, these findings outline a dynamic model for the use of DNMT3A and DNMT3B sequence specificity during gastrulation.
Identifiants
pubmed: 36510023
doi: 10.1038/s41594-022-00885-6
pii: 10.1038/s41594-022-00885-6
doi:
Substances chimiques
DNA Methyltransferase 3A
EC 2.1.1.37
DNA (Cytosine-5-)-Methyltransferases
EC 2.1.1.37
DNA
9007-49-2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1252-1265Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
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