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Dev Cell. 2016 Oct 10;39(1):87-103. doi: 10.1016/j.devcel.2016.08.008. Epub 2016 Sep 15.

Global Landscape and Regulatory Principles of DNA Methylation Reprogramming for Germ Cell Specification by Mouse Pluripotent Stem Cells.

Author information

1
Division of Epigenomics and Development, Medical Institute of Bioregulation, and Epigenome Network Research Center, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan; Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan.
2
Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; JST, ERATO, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
3
Medical Research Support Center, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
4
Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan; Institute for Integrated Cell-Material Sciences, Kyoto University, Yoshida-Ushinomiya-cho, Sakyo-ku, Kyoto 606-8501, Japan.
5
Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; Department of Developmental Stem Cell Biology, Faculty of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan; JST, PRESTO, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan.
6
Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; JST, ERATO, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan; Institute for Integrated Cell-Material Sciences, Kyoto University, Yoshida-Ushinomiya-cho, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: saitou@anat2.med.kyoto-u.ac.jp.
7
Division of Epigenomics and Development, Medical Institute of Bioregulation, and Epigenome Network Research Center, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan. Electronic address: hsasaki@bioreg.kyushu-u.ac.jp.

Abstract

Specification of primordial germ cells (PGCs) activates epigenetic reprogramming for totipotency, the elucidation of which remains a fundamental challenge. Here, we uncover regulatory principles for DNA methylation reprogramming during in vitro PGC specification, in which mouse embryonic stem cells (ESCs) are induced into epiblast-like cells (EpiLCs) and then PGC-like cells (PGCLCs). While ESCs reorganize their methylome to form EpiLCs, PGCLCs essentially dilute the EpiLC methylome at constant, yet different, rates between unique sequence regions and repeats. ESCs form hypomethylated domains around pluripotency regulators for their activation, whereas PGCLCs create demethylation-sensitive domains around developmental regulators by accumulating abundant H3K27me3 for their repression. Loss of PRDM14 globally upregulates methylation and diminishes the hypomethylated domains, but it preserves demethylation-sensitive domains. Notably, female ESCs form hypomethylated lamina-associated domains, while female PGCLCs effectively reverse such states into a more normal configuration. Our findings illuminate the unique orchestration of DNA methylation and histone modification reprogramming during PGC specification.

PMID:
27642137
DOI:
10.1016/j.devcel.2016.08.008
[Indexed for MEDLINE]
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