title: Glucose-dependent regulation of NR2F2 promoter and influence of SNP-rs3743462 on whole body insulin sensitivity.
abstract: BACKGROUND
  The Nuclear Receptor 2F2 (NR2F2/COUP-TFII) heterozygous knockout mice display low basal insulinemia and enhanced insulin sensitivity. We previously established that insulin represses NR2F2 gene expression in pancreatic β-cells. The cis-regulatory region of the NR2F2 promoter is unknown and its influence on metabolism in humans is poorly understood. The present study aimed to identify the regulatory regions that control NR2F2 gene transcription and to evaluate the effect of NR2F2 promoter variation on glucose homeostasis in humans.
  
  
  RESULTS
  Regulation of the NR2F2 promoter was assessed using gene reporter assays, ChIP and gel shift experiments. The effects of variation at SNP rs3743462 in NR2F2 on quantitative metabolic traits were studied in two European prospective cohorts. We identified a minimal promoter region that down-regulates NR2F2 expression by attenuating HNF4α activation in response to high glucose concentrations. Subjects of the French DESIR population, who carried the rs3743462 T-to-C polymorphism, located in the distal glucose-responsive promoter, displayed lower basal insulin levels and lower HOMA-IR index. The C-allele at rs3743462 was associated with increased NR2F2 binding and decreased NR2F2 gene expression.
  
  
  CONCLUSIONS
  The rs3743462 polymorphism affects glucose-responsive NR2F2 promoter regulation and thereby may influence whole-body insulin sensitivity, suggesting a role of NR2F2 in the control of glucose homeostasis in humans.
authors.affiliation: Department of Endocrinology, Metabolism and Cancer, Cochin Institute, CNRS (UMR 8104), Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Boutant
authors.forename: Oscar Henrique Pereira
authors.initials: OH
authors.lastname: Ramos
authors.forename: Cécile
authors.initials: C
authors.lastname: Lecoeur
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Vaillant
authors.forename: Julien
authors.initials: J
authors.lastname: Philippe
authors.forename: Pili
authors.initials: P
authors.lastname: Zhang
authors.forename: Anaïs
authors.initials: A
authors.lastname: Perilhou
authors.forename: Beatriz
authors.initials: B
authors.lastname: Valcarcel
authors.forename: Sylvain
authors.initials: S
authors.lastname: Sebert
authors.forename: Mario-Ritta
authors.initials: MR
authors.lastname: Jarvelin
authors.forename: Beverley
authors.initials: B
authors.lastname: Balkau
authors.forename: Donald
authors.initials: D
authors.lastname: Scott
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Martine
authors.initials: M
authors.lastname: Vaxillaire
authors.forename: Mireille
authors.initials: M
authors.lastname: Vasseur-Cognet
mesh_terms: D000328:Adult; D000818:Animals; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism; D051837:COUP Transcription Factor II / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D015331:Cohort Studies; D004247:DNA / Q000235:genetics; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics* / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011446:Prospective Studies; D012689:Sequence Homology, Nucleic Acid
chemical_list: D001786:Blood Glucose; D051837:COUP Transcription Factor II; D004247:DNA; D005947:Glucose; D051557:Hepatocyte Nuclear Factor 4; D007328:Insulin; C496592:HNF4A protein, human; C497587:Nr2f2 protein, mouse; C497588:Nr2f2 protein, rat; C095569:NR2F2 protein, human