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Esrrb is a direct Nanog target gene that can substitute for Nanog function in pluripotent cells.

TitleEsrrb is a direct Nanog target gene that can substitute for Nanog function in pluripotent cells.
Publication TypeJournal Article
Year of Publication2012
AuthorsFestuccia, N, Osorno, R, Halbritter, F, Karwacki-Neisius, V, Navarro, P, Colby, D, Wong, F, Yates, A, Tomlinson, SR, Chambers, I
JournalCell Stem Cell
Volume11
Issue4
Pagination477-90
Date Published2012 Oct 5
ISSN1875-9777
KeywordsAnimals, Cell Fusion, Cell Line, Cell Proliferation, Cell Survival, Chimera, Embryo Culture Techniques, Gene Expression Profiling, Gene Expression Regulation, Developmental, Homeodomain Proteins, Interleukin-6, Mice, Microarray Analysis, Mutant Proteins, Neural Stem Cells, Nuclear Reprogramming, Pluripotent Stem Cells, Receptors, Estrogen, Receptors, OSM-LIF, Transgenes
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.

DOI10.1016/j.stem.2012.08.002
Alternate JournalCell Stem Cell
PubMed ID23040477
PubMed Central IDPMC3473361
Grant List / / Medical Research Council / United Kingdom
/ / Wellcome Trust / United Kingdom