title: Esrrb is a direct Nanog target gene that can substitute for Nanog function in pluripotent cells.
abstract: Embryonic stem cell (ESC) self-renewal efficiency is determined by the level of Nanog expression. However, the mechanisms by which Nanog functions remain unclear, and in particular, direct Nanog target genes are uncharacterized. Here we investigate ESCs expressing different Nanog levels and Nanog(-/-) cells with distinct functionally inducible Nanog proteins to identify Nanog-responsive genes. Surprisingly, these constitute a minor fraction of genes that Nanog binds. Prominent among Nanog-reponsive genes is Estrogen-related receptor b (Esrrb). Nanog binds directly to Esrrb, enhances binding of RNAPolII, and stimulates Esrrb transcription. Overexpression of Esrrb in ESCs maintains cytokine-independent self-renewal and pluripotency. Remarkably, this activity is retained in Nanog(-/-) ESCs. Moreover, Esrrb can reprogram Nanog(-/-) EpiSCs and can rescue stalled reprogramming in Nanog(-/-) pre-iPSCs. Finally, Esrrb deletion abolishes the defining ability of Nanog to confer LIF-independent ESC self-renewal. These findings are consistent with the functional placement of Esrrb downstream of Nanog.
authors.affiliation: MRC Centre for Regenerative Medicine, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, Scotland.
authors.forename: Nicola
authors.initials: N
authors.lastname: Festuccia
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Osorno
authors.forename: Florian
authors.initials: F
authors.lastname: Halbritter
authors.forename: Violetta
authors.initials: V
authors.lastname: Karwacki-Neisius
authors.forename: Pablo
authors.initials: P
authors.lastname: Navarro
authors.forename: Douglas
authors.initials: D
authors.lastname: Colby
authors.forename: Frederick
authors.initials: F
authors.lastname: Wong
authors.forename: Adam
authors.initials: A
authors.lastname: Yates
authors.forename: Simon R
authors.initials: SR
authors.lastname: Tomlinson
authors.forename: Ian
authors.initials: I
authors.lastname: Chambers
mesh_terms: D000818:Animals; D002459:Cell Fusion; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D065150:Cellular Reprogramming / Q000235:genetics; D002678:Chimera; D046149:Embryo Culture Techniques; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D046228:Microarray Analysis; D050505:Mutant Proteins / Q000235:genetics; D000071317:Nanog Homeobox Protein; D058953:Neural Stem Cells / Q000502:physiology*; D039904:Pluripotent Stem Cells / Q000502:physiology*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D053606:Receptors, OSM-LIF / Q000235:genetics; D019076:Transgenes / Q000235:genetics
chemical_list: C098925:Esrrb protein, mouse; D018398:Homeodomain Proteins; D015850:Interleukin-6; D050505:Mutant Proteins; D000071317:Nanog Homeobox Protein; C475540:Nanog protein, mouse; D011960:Receptors, Estrogen; D053606:Receptors, OSM-LIF