title: Dax1 associates with Esrrb and regulates its function in embryonic stem cells.
abstract: Self-renewal capacity and pluripotency, which are controlled by the Oct3/4-centered transcriptional regulatory network, are major characteristics of embryonic stem (ES) cells. Nuclear hormone receptor Dax1 is one of the crucial factors in the network. Here, we identified an orphan nuclear receptor, Esrrb (estrogen-related receptor beta), as a Dax1-interacting protein. Interaction of Dax1 and Esrrb was mediated through LXXLL motifs of Dax1 and the activation- and ligand-binding domains of Esrrb. Furthermore, Esrrb enhanced the promoter activity of the Dax1 gene via direct binding to Esrrb-binding site 1 (ERRE1, where "ERRE" represents "Esrrb-responsive element") of the promoter. Expression of Dax1 was suppressed followed by Oct3/4 repression; however, overexpression of Esrrb maintained expression of Dax1 even in the absence of Oct3/4, indicating that Dax1 is a direct downstream target of Esrrb and that Esrrb can regulate Dax1 expression in an Oct3/4-independent manner. We also found that the transcriptional activity of Esrrb was repressed by Dax1. Furthermore, we revealed that Oct3/4, Dax1, and Esrrb have a competitive inhibition capacity for each complex. These data, together with previous findings, suggest that Dax1 functions as a negative regulator of Esrrb and Oct3/4, and these molecules form a regulatory loop for controlling the pluripotency and self-renewal capacity of ES cells.
authors.affiliation: Department of Stem Cell Biology, Kanazawa University, Ishikawa, Japan.
authors.forename: Kousuke
authors.initials: K
authors.lastname: Uranishi
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Akagi
authors.forename: Chuanhai
authors.initials: C
authors.lastname: Sun
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Koide
authors.forename: Takashi
authors.initials: T
authors.lastname: Yokota
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D057137:DAX-1 Orphan Nuclear Receptor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053595:Embryonic Stem Cells; D004707:Endoderm / Q000378:metabolism; D015870:Gene Expression; D051379:Mice; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011960:Receptors, Estrogen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques; D000099254:Organic Cation Transporter 3
chemical_list: D015415:Biomarkers; D057137:DAX-1 Orphan Nuclear Receptor; D027701:Organic Cation Transport Proteins; D011960:Receptors, Estrogen; D000099254:Organic Cation Transporter 3; C098925:Esrrb protein, mouse; C539966:Nr0b1 protein, mouse