Identification of distinct loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development

Masaki Yagi, Mio Kabata, Akito Tanaka, Tomoyo Ukai, Sho Ohta, Kazuhiko Nakabayashi, Masahito Shimizu, Kenichiro Hata, Alexander Meissner, Takuya Yamamoto () and Yasuhiro Yamada ()
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Masaki Yagi: University of Tokyo
Mio Kabata: Kyoto University
Akito Tanaka: Kyoto University
Tomoyo Ukai: University of Tokyo
Sho Ohta: University of Tokyo
Kazuhiko Nakabayashi: National Research Institute for Child Health and Development
Masahito Shimizu: Gifu University Graduate School of Medicine
Kenichiro Hata: National Research Institute for Child Health and Development
Alexander Meissner: Max Planck Institute for Molecular Genetics
Takuya Yamamoto: Kyoto University
Yasuhiro Yamada: University of Tokyo

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract De novo establishment of DNA methylation is accomplished by DNMT3A and DNMT3B. Here, we analyze de novo DNA methylation in mouse embryonic fibroblasts (2i-MEFs) derived from DNA-hypomethylated 2i/L ES cells with genetic ablation of Dnmt3a or Dnmt3b. We identify 355 and 333 uniquely unmethylated genes in Dnmt3a and Dnmt3b knockout (KO) 2i-MEFs, respectively. We find that Dnmt3a is exclusively required for de novo methylation at both TSS regions and gene bodies of Polycomb group (PcG) target developmental genes, while Dnmt3b has a dominant role on the X chromosome. Consistent with this, tissue-specific DNA methylation at PcG target genes is substantially reduced in Dnmt3a KO embryos. Finally, we find that human patients with DNMT3 mutations exhibit reduced DNA methylation at regions that are hypomethylated in Dnmt3 KO 2i-MEFs. In conclusion, here we report a set of unique de novo DNA methylation target sites for both DNMT3 enzymes during mammalian development that overlap with hypomethylated sites in human patients.

Date: 2020
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DOI: 10.1038/s41467-020-16989-w

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