Combined Loss of JMJD1A and JMJD1B Reveals Critical Roles for H3K9 Demethylation in the Maintenance of Embryonic Stem Cells and Early Embryogenesis

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  • Kuroki, Shunsuke
    Institute of Advanced Medical Sciences, Tokushima University
  • Nakai, Yuji
    Institute for Food Sciences, Hirosaki University
  • Maeda, Ryo
    Institute of Advanced Medical Sciences, Tokushima University
  • Okashita, Naoki
    Institute of Advanced Medical Sciences, Tokushima University
  • Akiyoshi, Mika
    Experimental Research Center for Infectious Diseases, Institute for Virus Research, Kyoto University
  • Yamaguchi, Yutaro
    Experimental Research Center for Infectious Diseases, Institute for Virus Research, Kyoto University
  • Kitano, Satsuki
    Experimental Research Center for Infectious Diseases, Institute for Virus Research, Kyoto University
  • Miyachi, Hitoshi
    Experimental Research Center for Infectious Diseases, Institute for Virus Research, Kyoto University
  • Nakato, Ryuichiro
    Research Center for Epigenetic Disease, The University of Tokyo
  • Ichiyanagi, Kenji
    Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University
  • Shirahige, Katsuhiko
    Research Center for Epigenetic Disease, The University of Tokyo
  • Kimura, Hiroshi
    Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology
  • Shinkai, Yoichi
    Cellular Memory Laboratory, RIKEN Advanced Science Institute
  • Tachibana, Makoto
    Institute of Advanced Medical Sciences, Tokushima University・Experimental Research Center for Infectious Diseases, Institute for Virus Research, Kyoto University

Abstract

Histone H3 lysine 9 (H3K9) methylation is unevenly distributed in mammalian chromosomes. However, the molecular mechanism controlling the uneven distribution and its biological significance remain to be elucidated. Here, we show that JMJD1A and JMJD1B preferentially target H3K9 demethylation of gene-dense regions of chromosomes, thereby establishing an H3K9 hypomethylation state in euchromatin. JMJD1A/JMJD1B-deficient embryos died soon after implantation accompanying epiblast cell death. Furthermore, combined loss of JMJD1A and JMJD1B caused perturbed expression of metabolic genes and rapid cell death in embryonic stem cells (ESCs). These results indicate that JMJD1A/JMJD1B-meditated H3K9 demethylation has critical roles for early embryogenesis and ESC maintenance. Finally, genetic rescue experiments clarified that H3K9 overmethylation by G9A was the cause of the cell death and perturbed gene expression of JMJD1A/JMJD1B-depleted ESCs. We summarized that JMJD1A and JMJD1B, in combination, ensure early embryogenesis and ESC viability by establishing the correct H3K9 methylated epigenome.

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