title: Global Landscape and Regulatory Principles of DNA Methylation Reprogramming for Germ Cell Specification by Mouse Pluripotent Stem Cells.
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.
authors.affiliation: 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.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Shirane
authors.affiliation: 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.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Kurimoto
authors.affiliation: 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.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Yabuta
authors.affiliation: 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.
authors.forename: Masashi
authors.initials: M
authors.lastname: Yamaji
authors.affiliation: Medical Research Support Center, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Satoh
authors.affiliation: Medical Research Support Center, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Ito
authors.affiliation: 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.
authors.forename: Akira
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: 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.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: 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.
authors.forename: Mitinori
authors.initials: M
authors.lastname: Saitou
authors.affiliation: 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.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sasaki
mesh_terms: D000818:Animals; D065150:Cellular Reprogramming / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D004268:DNA-Binding Proteins; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005854:Germ Cells / Q000166:cytology* / Q000378:metabolism*; D005855:Germ Layers / Q000166:cytology; D006657:Histones / Q000378:metabolism; D055442:Metabolome; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D016601:RNA-Binding Proteins; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; C531066:Prdm14 protein, mouse; D016601:RNA-Binding Proteins; D014157:Transcription Factors