title: H3K4/H3K9me3 Bivalent Chromatin Domains Targeted by Lineage-Specific DNA Methylation Pauses Adipocyte Differentiation.
abstract: Bivalent H3K4me3 and H3K27me3 chromatin domains in embryonic stem cells keep active developmental regulatory genes expressed at very low levels and poised for activation. Here, we show an alternative and previously unknown bivalent modified histone signature in lineage-committed mesenchymal stem cells and preadipocytes that pairs H3K4me3 with H3K9me3 to maintain adipogenic master regulatory genes (Cebpa and Pparg) expressed at low levels yet poised for activation when differentiation is required. We show lineage-specific gene-body DNA methylation recruits H3K9 methyltransferase SETDB1, which methylates H3K9 immediately downstream of transcription start sites marked with H3K4me3 to establish the bivalent domain. At the Cebpa locus, this prevents transcription factor C/EBPβ binding, histone acetylation, and further H3K4me3 deposition and is associated with pausing of RNA polymerase II, which limits Cebpa gene expression and adipogenesis.
authors.affiliation: Division of Metabolic Medicine, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan; The Translational Systems Biology and Medicine Initiative (TSBMI), Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan. Electronic address: matsumura-y@lsbm.org.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Matsumura
authors.affiliation: Genome Science Division, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Nakaki
authors.affiliation: Division of Metabolic Medicine, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan; The Translational Systems Biology and Medicine Initiative (TSBMI), Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Inagaki
authors.affiliation: Division of Metabolic Medicine, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan; Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Science, Tokyo 192-0392, Japan.
authors.forename: Ayano
authors.initials: A
authors.lastname: Yoshida
authors.affiliation: Division of Metabolic Medicine, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kano
authors.affiliation: Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Division of Metabolic Medicine, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan; Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan; The Translational Systems Biology and Medicine Initiative (TSBMI), Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Genome Science Division, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Tsutsumi
authors.affiliation: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan.
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Nakao
authors.affiliation: Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Takefumi
authors.initials: T
authors.lastname: Doi
authors.affiliation: Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Science, Tokyo 192-0392, Japan.
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Fukami
authors.affiliation: Metabolic Disease Program, Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA.
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Osborne
authors.affiliation: Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.affiliation: Genome Science Division, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan; The Translational Systems Biology and Medicine Initiative (TSBMI), Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.affiliation: Division of Metabolic Medicine, The University of Tokyo, 4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan; The Translational Systems Biology and Medicine Initiative (TSBMI), Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan. Electronic address: jmsakai-tky@umin.ac.jp.
authors.forename: Juro
authors.initials: J
authors.lastname: Sakai
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology* / Q000502:physiology; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D019175:DNA Methylation; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000235:genetics*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism*; D017434:Protein Structure, Tertiary
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; D002843:Chromatin; D006657:Histones; D047495:PPAR gamma; D011495:Histone-Lysine N-Methyltransferase; C516239:SETDB1 protein, mouse
keywords: DNA methylation; H3K27me3; H3K4me3; H3K9me3; Histone methylation; RNA polymerase II; adipogenesis; bivalent chromatin domains; epigenome; gene-body methylation; lineage commitment