TY - JOUR
T1 - Glucose-dependent regulation of NR2F2 promoter and influence of SNP-rs3743462 on whole body insulin sensitivity
AU - Boutant, Marie
AU - Ramos, Oscar Henrique Pereira
AU - Lecoeur, Cécile
AU - Vaillant, Emmanuel
AU - Philippe, Julien
AU - Zhang, Pili
AU - Perilhou, Anaïs
AU - Valcarcel, Beatriz
AU - Sebert, Sylvain
AU - Jarvelin, Mario Ritta
AU - Balkau, Beverley
AU - Scott, Donald
AU - Froguel, Philippe
AU - Vaxillaire, Martine
AU - Vasseur-Cognet, Mireille
N1 - Funding Information:
The authors have the following interest: This work was supported by grants from Merck Sharp & Dohme. The D.E.S.I.R. study has been supported by INSERM contracts with CNAMTS, Lilly, Novartis Pharma, and Sanofiaventis, ONIVINS, Ardix Medical, Bayer Diagnostics, Becton Dickinson, Cardionics, Merck Santé, Novo Nordisk, Pierre Fabre, Roche, and Topcon. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials, as detailed online in the guide for authors.
PY - 2012/5/14
Y1 - 2012/5/14
N2 - 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. Methodology/Principal Findings: 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/Significance: 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.
AB - 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. Methodology/Principal Findings: 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/Significance: 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.
UR - http://www.scopus.com/inward/record.url?scp=84861010435&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0035810
DO - 10.1371/journal.pone.0035810
M3 - Article
C2 - 22606236
AN - SCOPUS:84861010435
SN - 1932-6203
VL - 7
JO - PLoS ONE
JF - PLoS ONE
IS - 5
M1 - e35810
ER -