title: The pluripotency factor Nanog regulates pericentromeric heterochromatin organization in mouse embryonic stem cells.
abstract: An open and decondensed chromatin organization is a defining property of pluripotency. Several epigenetic regulators have been implicated in maintaining an open chromatin organization, but how these processes are connected to the pluripotency network is unknown. Here, we identified a new role for the transcription factor NANOG as a key regulator connecting the pluripotency network with constitutive heterochromatin organization in mouse embryonic stem cells. Deletion of Nanog leads to chromatin compaction and the remodeling of heterochromatin domains. Forced expression of NANOG in epiblast stem cells is sufficient to decompact chromatin. NANOG associates with satellite repeats within heterochromatin domains, contributing to an architecture characterized by highly dispersed chromatin fibers, low levels of H3K9me3, and high major satellite transcription, and the strong transactivation domain of NANOG is required for this organization. The heterochromatin-associated protein SALL1 is a direct cofactor for NANOG, and loss of Sall1 recapitulates the Nanog-null phenotype, but the loss of Sall1 can be circumvented through direct recruitment of the NANOG transactivation domain to major satellites. These results establish a direct connection between the pluripotency network and chromatin organization and emphasize that maintaining an open heterochromatin architecture is a highly regulated process in embryonic stem cells.
authors.affiliation: Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, United Kingdom;
authors.forename: Clara Lopes
authors.initials: CL
authors.lastname: Novo
authors.affiliation: Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario MSG 1L7, Canada; Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
authors.forename: Calvin
authors.initials: C
authors.lastname: Tang
authors.affiliation: Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario MSG 1L7, Canada;
authors.forename: Kashif
authors.initials: K
authors.lastname: Ahmed
authors.affiliation: Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
authors.forename: Ugljesa
authors.initials: U
authors.lastname: Djuric
authors.affiliation: Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario MSG 1L7, Canada; Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
authors.forename: Eden
authors.initials: E
authors.lastname: Fussner
authors.affiliation: MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, United Kingdom;
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Mullin
authors.affiliation: Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, United Kingdom;
authors.forename: Natasha P
authors.initials: NP
authors.lastname: Morgan
authors.affiliation: Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, United Kingdom;
authors.forename: Jasvinder
authors.initials: J
authors.lastname: Hayre
authors.affiliation: Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, United Kingdom;
authors.forename: Arnold R
authors.initials: AR
authors.lastname: Sienerth
authors.affiliation: Nuclear Dynamics Programme, The Babraham Institute, Cambridge, CB22 3AT, United Kingdom;
authors.forename: Sarah
authors.initials: S
authors.lastname: Elderkin
authors.affiliation: Department of Kidney Development, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan;
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Nishinakamura
authors.affiliation: MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, United Kingdom;
authors.forename: Ian
authors.initials: I
authors.lastname: Chambers
authors.affiliation: Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
authors.forename: James
authors.initials: J
authors.lastname: Ellis
authors.affiliation: Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario MSG 1L7, Canada; Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
authors.forename: David P
authors.initials: DP
authors.lastname: Bazett-Jones
authors.affiliation: Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, United Kingdom; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, United Kingdom; Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Rugg-Gunn
mesh_terms: D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D015536:Down-Regulation; D017353:Gene Deletion; D006570:Heterochromatin / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000502:physiology*; D000071317:Nanog Homeobox Protein / Q000235:genetics / Q000378:metabolism*; D000072417:Protein Domains; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D002843:Chromatin; D006570:Heterochromatin; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; C491254:Sall1 protein, mouse; D014157:Transcription Factors
keywords: embryonic stem cells; heterochromatin; nuclear organization; pluripotency