2. Academic Validation
  3. Identification of distinct loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development

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

  • Nat Commun. 2020 Jun 24;11(1):3199. doi: 10.1038/s41467-020-16989-w.
Masaki Yagi # 1 2,  Mio Kabata # 3 4,  Akito Tanaka 3,  Tomoyo Ukai 1,  Sho Ohta 1,  Kazuhiko Nakabayashi 5,  Masahito Shimizu 4,  Kenichiro Hata 5,  Alexander Meissner 6 7 8,  Takuya Yamamoto 9 10 11 12,  Yasuhiro Yamada 13 14
Affiliations

Affiliations

  • 1 Division of Stem Cell Pathology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan.
  • 2 Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, 02114, USA.
  • 3 Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan.
  • 4 Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, 501-1194, Japan.
  • 5 Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan.
  • 6 Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, 14195, Germany.
  • 7 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA.
  • 8 Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
  • 9 Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan. [email protected].
  • 10 AMED-CREST, AMED 1-7-1 Otemachi, Tokyo, 100-0004, Japan. [email protected].
  • 11 Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, 606-8501, Japan. [email protected].
  • 12 Medical-risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, 606-8507, Japan. [email protected].
  • 13 Division of Stem Cell Pathology, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan. [email protected].
  • 14 AMED-CREST, AMED 1-7-1 Otemachi, Tokyo, 100-0004, Japan. [email protected].
  • # Contributed equally.
PMID: 32581223 DOI: 10.1038/s41467-020-16989-w
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.

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