title: Tsix RNA and the germline factor, PRDM14, link X reactivation and stem cell reprogramming.
abstract: Transitions between pluripotent and differentiated states are marked by dramatic epigenetic changes. Cellular differentiation is tightly linked to X chromosome inactivation (XCI), whereas reprogramming to induced pluripotent stem cells (iPSCs) is associated with X chromosome reactivation (XCR). XCR reverses the silent state of the inactive X, occurring in mouse blastocysts and germ cells. In spite of its importance, little is known about underlying mechanisms. Here, we examine the role of the long noncoding Tsix RNA and the germline factor, PRDM14. In blastocysts, XCR is perturbed by mutation of either Tsix or Prdm14. In iPSCs, XCR is disrupted only by PRDM14 deficiency, which also affects iPSC derivation and maintenance. We show that Tsix and PRDM14 directly link XCR to pluripotency: first, PRDM14 represses Rnf12 by recruiting polycomb repressive complex 2; second, Tsix enables PRDM14 to bind Xist. Thus, our study provides functional and mechanistic links between cellular and X chromosome reprogramming.
authors.affiliation: Howard Hughes Medical Institute, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Payer
authors.affiliation: Howard Hughes Medical Institute, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Rosenberg
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: 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: Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin Yoshida, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Michiyo
authors.initials: M
authors.lastname: Koyanagi-Aoi
authors.affiliation: Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin Yoshida, Sakyo-ku, Kyoto 606-8507, Japan; JST, PRESTO, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin Yoshida, Sakyo-ku, Kyoto 606-8507, Japan; Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamanaka
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 Yoshida, 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: Mitinori
authors.initials: M
authors.lastname: Saitou
authors.affiliation: Howard Hughes Medical Institute, Boston, MA 02114, USA; Department of Genetics, Harvard Medical School, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: lee@molbio.mgh.harvard.edu.
authors.forename: Jeannie T
authors.initials: JT
authors.lastname: Lee
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D065150:Cellular Reprogramming; D004268:DNA-Binding Proteins; D010064:Embryo Implantation; D053595:Embryonic Stem Cells / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D049951:X Chromosome Inactivation
chemical_list: D004268:DNA-Binding Proteins; C531066:Prdm14 protein, mouse; D062085:RNA, Long Noncoding; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C465658:Tsix transcript, mouse; C077885:XIST non-coding RNA; D063151:Polycomb Repressive Complex 2; C120758:Rlim protein, mouse; D044767:Ubiquitin-Protein Ligases