title: A Structural Investigation into Oct4 Regulation by Orphan Nuclear Receptors, Germ Cell Nuclear Factor (GCNF), and Liver Receptor Homolog-1 (LRH-1).
abstract: Oct4 is a transcription factor required for maintaining pluripotency and self-renewal in stem cells. Prior to differentiation, Oct4 must be silenced to allow for the development of the three germ layers in the developing embryo. This fine-tuning is controlled by the nuclear receptors (NRs), liver receptor homolog-1 (LRH-1) and germ cell nuclear factor (GCNF). Liver receptor homolog-1 is responsible for driving the expression of Oct4 where GCNF represses its expression upon differentiation. Both receptors bind to a DR0 motif located within the Oct4 promoter. Here, we present the first structure of mouse GCNF DNA-binding domain in complex with the Oct4 DR0. The overall structure revealed two molecules bound in a head-to-tail fashion on opposite sides of the DNA. Additionally, we solved the structure of the human LRH-1 DNA-binding domain bound to the same element. We explore the structural elements that govern Oct4 recognition by these two NRs.
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, 30322 USA.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Weikum
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, 30322 USA.
authors.forename: Micheal L
authors.initials: ML
authors.lastname: Tuntland
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, 30322 USA.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Murphy
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, 30322 USA. Electronic address: eortlun@emory.edu.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Ortlund
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D057136:Nuclear Receptor Subfamily 6, Group A, Member 1 / Q000737:chemistry* / Q000378:metabolism*; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis* / Q000737:chemistry*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000378:metabolism*
chemical_list: C082631:NR5A2 protein, human; C539954:Nr6a1 protein, mouse; D057136:Nuclear Receptor Subfamily 6, Group A, Member 1; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D004247:DNA
keywords: Oct4 regulation; X-ray crystallography; germ cell nuclear factor; liver receptor homolog-1; nuclear receptors