title: Esrrb is a pivotal target of the Gsk3/Tcf3 axis regulating embryonic stem cell self-renewal.
abstract: Inhibition of glycogen synthase kinase-3 (Gsk3) supports mouse embryonic stem cells (ESCs) by modulating Tcf3, but the critical targets downstream of Tcf3 are unclear. We analyzed the intersection between genome localization and transcriptome data sets to identify genes repressed by Tcf3. Among these, manipulations of Esrrb gave distinctive phenotypes in functional assays. Knockdown and knockout eliminated response to Gsk3 inhibition, causing extinction of pluripotency markers and loss of colony forming capability. Conversely, forced expression phenocopied Gsk3 inhibition or Tcf3 deletion by suppressing differentiation and sustaining self-renewal. Thus the nuclear receptor Esrrb is necessary and sufficient to mediate self-renewal downstream of Gsk3 inhibition. Leukaemia inhibitory factor (LIF) regulates ESCs through Stat3, independently of Gsk3 inhibition. Consistent with parallel operation, ESCs in LIF accommodated Esrrb deletion and remained pluripotent. These findings highlight a key role for Esrrb in regulating the naive pluripotent state and illustrate compensation among the core pluripotency factors.
authors.affiliation: Wellcome Trust - Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge UK.
authors.forename: Graziano
authors.initials: G
authors.lastname: Martello
authors.forename: Toshimi
authors.initials: T
authors.lastname: Sugimoto
authors.forename: Evangelia
authors.initials: E
authors.lastname: Diamanti
authors.forename: Anagha
authors.initials: A
authors.lastname: Joshi
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hannah
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ohtsuka
authors.forename: Berthold
authors.initials: B
authors.lastname: Göttgens
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Niwa
authors.forename: Austin
authors.initials: A
authors.lastname: Smith
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D016678:Genome; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D053605:Leukemia Inhibitory Factor / Q000378:metabolism; D051379:Mice; D039904:Pluripotent Stem Cells / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D038362:Glycogen Synthase Kinase 3; D053605:Leukemia Inhibitory Factor; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; C098925:Esrrb protein, mouse; C507837:LIF protein, human; C075668:Tcf3 protein, mouse