DNA methyltransferases 3A and 3B target specific sequences during mouse gastrulation

Item Type:	Article
Title:	DNA methyltransferases 3A and 3B target specific sequences during mouse gastrulation
Creators Name:	Mukamel, Z. and Lifshitz, A. and Mittnenzweig, M. and Chomsky, E. and Schwartzman, O. and Ben-Kiki, O. and Zerbib, M. and Tanay, A.
Abstract:	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.
Keywords:	DNA, DNA (Cytosine-5-)-Methyltransferases, DNA Methylation, DNA Methyltransferase 3A, Mammalian Embryo, Gastrulation, Mammals, Animals, Mice
Source:	Nature Structural & Molecular Biology
ISSN:	1545-9993
Publisher:	Nature Publishing Group
Volume:	29
Number:	12
Page Range:	1252-1265
Date:	December 2022
Official Publication:	https://doi.org/10.1038/s41594-022-00885-6
PubMed:	View item in PubMed

Repository Staff Only: item control page