title: Functional Divergence of the Nuclear Receptor NR2C1 as a Modulator of Pluripotentiality During Hominid Evolution.
abstract: Genes encoding nuclear receptors (NRs) are attractive as candidates for investigating the evolution of gene regulation because they (1) have a direct effect on gene expression and (2) modulate many cellular processes that underlie development. We employed a three-phase investigation linking NR molecular evolution among primates with direct experimental assessment of NR function. Phase 1 was an analysis of NR domain evolution and the results were used to guide the design of phase 2, a codon-model-based survey for alterations of natural selection within the hominids. By using a series of reliability and robustness analyses we selected a single gene, NR2C1, as the best candidate for experimental assessment. We carried out assays to determine whether changes between the ancestral and extant NR2C1s could have impacted stem cell pluripotency (phase 3). We evaluated human, chimpanzee, and ancestral NR2C1 for transcriptional modulation of Oct4 and Nanog (key regulators of pluripotency and cell lineage commitment), promoter activity for Pepck (a proxy for differentiation in numerous cell types), and average size of embryological stem cell colonies (a proxy for the self-renewal capacity of pluripotent cells). Results supported the signal for alteration of natural selection identified in phase 2. We suggest that adaptive evolution of gene regulation has impacted several aspects of pluripotentiality within primates. Our study illustrates that the combination of targeted evolutionary surveys and experimental analysis is an effective strategy for investigating the evolution of gene regulation with respect to developmental phenotypes.
authors.affiliation: Center for the Advanced Study of Human Paleobiology, George Washington University, Washington, DC 20052 George Washington Institute for Neuroscience, George Washington University, Washington, DC 20052 Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892 JenniferLBaker7@gmail.com J.Bielawski@dal.ca.
authors.forename: Jennifer L
authors.identifier: 0000-0002-5192-2377
authors.initials: JL
authors.lastname: Baker
authors.affiliation: Department of Biology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Dunn
authors.affiliation: Department of Mathematics and Statistics, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2.
authors.forename: Joseph
authors.initials: J
authors.lastname: Mingrone
authors.affiliation: Center for the Advanced Study of Human Paleobiology, George Washington University, Washington, DC 20052 Human Origins Program, National Museum of Natural History, Smithsonian Institution, Washington, DC 20560.
authors.forename: Bernard A
authors.initials: BA
authors.lastname: Wood
authors.affiliation: Department of Anatomy and Regenerative Biology, George Washington University, Washington, DC 20052.
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Karpinski
authors.affiliation: Center for the Advanced Study of Human Paleobiology, George Washington University, Washington, DC 20052 George Washington Institute for Neuroscience, George Washington University, Washington, DC 20052.
authors.forename: Chet C
authors.initials: CC
authors.lastname: Sherwood
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Champaign, Illinois 61801 Institute for Genomic Biology, University of Illinois Urbana-Champaign, Champaign, Illinois 61801.
authors.forename: Derek E
authors.initials: DE
authors.lastname: Wildman
authors.affiliation: George Washington Institute for Neuroscience, George Washington University, Washington, DC 20052 Department of Pharmacology and Physiology, George Washington University, Washington, DC 20052.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Maynard
authors.affiliation: Department of Biology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2 Department of Mathematics and Statistics, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2 JenniferLBaker7@gmail.com J.Bielawski@dal.ca.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Bielawski
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D017124:Conserved Sequence; D019143:Evolution, Molecular; D015186:Hominidae / Q000235:genetics*; D006801:Humans; D051379:Mice; D000071317:Nanog Homeobox Protein / Q000235:genetics / Q000378:metabolism; D057107:Nuclear Receptor Subfamily 2, Group C, Member 1 / Q000737:chemistry / Q000235:genetics*; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D000072417:Protein Domains
chemical_list: D000071317:Nanog Homeobox Protein; D057107:Nuclear Receptor Subfamily 2, Group C, Member 1; D050814:Octamer Transcription Factor-3; D019764:Phosphoenolpyruvate Carboxykinase (ATP)
keywords: NR2C1; ancestral gene reconstruction (AGR); codon models; hominid evolutionary survey; nuclear receptors; pluripotentiality; testicular receptor 2 (TR2)