title: Ctbp2 Modulates NuRD-Mediated Deacetylation of H3K27 and Facilitates PRC2-Mediated H3K27me3 in Active Embryonic Stem Cell Genes During Exit from Pluripotency.
abstract: For cells to exit from pluripotency and commit to a lineage, the circuitry of a core transcription factor (CTF) network must be extinguished in an orderly manner through epigenetic modifications. However, how this choreographed epigenetic remodeling at active embryonic stem cell (ESC) genes occurs during differentiation is poorly understood. In this study, we demonstrate that C-terminal binding protein 2 (Ctbp2) regulates nucleosome remodeling and deacetylation (NuRD)-mediated deacetylation of H3K27 and facilitates recruitment of polycomb repressive complex 2 (PRC2)-mediated H3K27me3 in active ESC genes for exit from pluripotency during differentiation. By genomewide analysis, we found that Ctbp2 resides in active ESC genes and co-occupies regions with ESC CTFs in undifferentiated ESCs. Furthermore, ablation of Ctbp2 effects inappropriate gene silencing in ESCs by sustaining high levels of H3K27ac and impeding H3K27me3 in active ESC genes, thereby sustaining ESC maintenance during differentiation. Thus, Ctbp2 preoccupies regions in active genes with the NuRD complex in undifferentiated ESCs that are directed toward H3K27me3 by PRC2 to induce stable silencing, which is pivotal for natural lineage commitment.
authors.affiliation: National Creative Research Center for Epigenome Reprogramming Network, Department of Biomedical Sciences, Ischemic/Hypoxic Disease Institute, Seoul, Republic of Korea.
authors.forename: Tae Wan
authors.initials: TW
authors.lastname: Kim
authors.affiliation: National Creative Research Center for Epigenome Reprogramming Network, Department of Biomedical Sciences, Ischemic/Hypoxic Disease Institute, Seoul, Republic of Korea.
authors.forename: Byung-Hee
authors.initials: BH
authors.lastname: Kang
authors.affiliation: National Creative Research Center for Epigenome Reprogramming Network, Department of Biomedical Sciences, Ischemic/Hypoxic Disease Institute, Seoul, Republic of Korea.|Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, Republic of Korea.
authors.forename: Hyonchol
authors.initials: H
authors.lastname: Jang
authors.affiliation: National Creative Research Center for Epigenome Reprogramming Network, Department of Biomedical Sciences, Ischemic/Hypoxic Disease Institute, Seoul, Republic of Korea.
authors.forename: Sojung
authors.initials: S
authors.lastname: Kwak
authors.affiliation: National Creative Research Center for Epigenome Reprogramming Network, Department of Biomedical Sciences, Ischemic/Hypoxic Disease Institute, Seoul, Republic of Korea.
authors.forename: Jihoon
authors.initials: J
authors.lastname: Shin
authors.affiliation: National Creative Research Center for Epigenome Reprogramming Network, Department of Biomedical Sciences, Ischemic/Hypoxic Disease Institute, Seoul, Republic of Korea.
authors.forename: Hyunsoo
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Sang-Eun
authors.initials: SE
authors.lastname: Lee
authors.affiliation: National Creative Research Center for Epigenome Reprogramming Network, Department of Biomedical Sciences, Ischemic/Hypoxic Disease Institute, Seoul, Republic of Korea.
authors.forename: Soon-Min
authors.initials: SM
authors.lastname: Lee
authors.affiliation: National Creative Research Center for Epigenome Reprogramming Network, Department of Biomedical Sciences, Ischemic/Hypoxic Disease Institute, Seoul, Republic of Korea.
authors.forename: Jong-Hyuk
authors.initials: JH
authors.lastname: Lee
authors.affiliation: National Creative Research Center for Epigenome Reprogramming Network, Department of Biomedical Sciences, Ischemic/Hypoxic Disease Institute, Seoul, Republic of Korea.
authors.forename: Jae-Hwan
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Medical Genomic Research Center, KRIBB, Daejeon, Republic of Korea.
authors.forename: Seon-Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Cho
authors.affiliation: Seoul National University Biomedical Informatics (SNUBI), Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Ju Han
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Biomedical Center for Animal Resource Development, N-Bio, Suwon, Republic of Korea.
authors.forename: Keun Soo
authors.initials: KS
authors.lastname: Park
authors.affiliation: Biomedical Center for Animal Resource Development, N-Bio, Suwon, Republic of Korea.
authors.forename: Jeong-Hwan
authors.initials: JH
authors.lastname: Che
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science, Seoul National University, Seoul, Republic of Korea.
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Han
authors.affiliation: Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul, Republic of Korea.
authors.forename: Min Jueng
authors.initials: MJ
authors.lastname: Kang
authors.affiliation: Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul, Republic of Korea.
authors.forename: Eugene C
authors.initials: EC
authors.lastname: Yi
authors.affiliation: National Creative Research Center for Epigenome Reprogramming Network, Department of Biomedical Sciences, Ischemic/Hypoxic Disease Institute, Seoul, Republic of Korea.|Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul, Republic of Korea.
authors.forename: Hong-Duk
authors.initials: HD
authors.lastname: Youn
mesh_terms: D000429:Alcohol Oxidoreductases; D000818:Animals; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly / Q000502:physiology; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000502:physiology*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D009707:Nucleosomes / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D006657:Histones; D009707:Nucleosomes; D010750:Phosphoproteins; D012097:Repressor Proteins; D000429:Alcohol Oxidoreductases; C111341:Ctbp2 protein, mouse; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex
keywords: Active embryonic stem cell genes; C-terminal binding protein; Core transcription factor; Embryonic stem cells; Exit from pluripotency; H3K27 acetylation and trimethylation; Nucleosome remodeling and deacetylation complex; Polycomb repressive complex 2