title: Ncoa3 functions as an essential Esrrb coactivator to sustain embryonic stem cell self-renewal and reprogramming.
abstract: Embryonic stem cell (ESC) pluripotency depends on a well-characterized gene regulatory network centered on Oct4, Sox2, and Nanog. In contrast, little is known about the identity of the key coregulators and the mechanisms by which they may potentiate transcription in ESCs. Alongside core transcription factors, the orphan nuclear receptor Esrrb (estrogen-related receptor β) is vital for the maintenance of ESC identity and furthermore is uniquely associated with the basal transcription machinery. Here, we show that Ncoa3, an essential coactivator, is required to mediate Esrrb function in ESCs. Ncoa3 interacts with Esrrb via its ligand-binding domain and bridges Esrrb to RNA polymerase II complexes. Functionally, Ncoa3 is critical for both the induction and maintenance of pluripotency. Through chromatin immunoprecipitation (ChIP) sequencing and microarray experiments, we further demonstrate that Ncoa3 shares overlapping gene regulatory functions with Esrrb and cooperates genome-wide with the Oct4-Sox2-Nanog circuitry at active enhancers to up-regulate genes involved in self-renewal and pluripotency. We propose an integrated model of transcriptional and coactivator control, mediated by Ncoa3, for the maintenance of ESC self-renewal and somatic cell reprogramming.
authors.affiliation: Institute of Reproductive and Developmental Biology, Imperial College, London, United Kingdom.
authors.forename: Michelle
authors.initials: M
authors.lastname: Percharde
authors.forename: Fabrice
authors.initials: F
authors.lastname: Lavial
authors.forename: Jia-Hui
authors.initials: JH
authors.lastname: Ng
authors.forename: Vibhor
authors.initials: V
authors.lastname: Kumar
authors.forename: Rute A
authors.initials: RA
authors.lastname: Tomaz
authors.forename: Nadine
authors.initials: N
authors.lastname: Martin
authors.forename: Jia-Chi
authors.initials: JC
authors.lastname: Yeo
authors.forename: Jesús
authors.initials: J
authors.lastname: Gil
authors.forename: Shyam
authors.initials: S
authors.lastname: Prabhakar
authors.forename: Huck-Hui
authors.initials: HH
authors.lastname: Ng
authors.forename: Malcolm G
authors.initials: MG
authors.lastname: Parker
authors.forename: Véronique
authors.initials: V
authors.lastname: Azuara
mesh_terms: D000818:Animals; D019556:COS Cells; D049109:Cell Proliferation; D065150:Cellular Reprogramming / Q000235:genetics*; D002522:Chlorocebus aethiops; D053595:Embryonic Stem Cells / Q000166:cytology*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D016678:Genome / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D056921:Nuclear Receptor Coactivator 3 / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*
chemical_list: C098925:Esrrb protein, mouse; D011960:Receptors, Estrogen; C538867:Ncoa3 protein, mouse; D056921:Nuclear Receptor Coactivator 3