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Glucose-dependent regulation of NR2F2 promoter and influence of SNP-rs3743462 on whole body insulin sensitivity

Boutant, M and Ramos, OHP and Lecoeur, C and Vaillant, E and Philippe, J and Zhang, P and Perilhou, A and Valcarcel, B and Sebert, S and Jarvelin, MR and Balkau, B and Scott, D and Froguel, P and Vaxillaire, M and Vasseur-Cognet, M (2012) Glucose-dependent regulation of NR2F2 promoter and influence of SNP-rs3743462 on whole body insulin sensitivity. PLoS ONE, 7 (5).

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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. © 2012 Boutant et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Boutant, M
Ramos, OHP
Lecoeur, C
Vaillant, E
Philippe, J
Zhang, P
Perilhou, A
Valcarcel, B
Sebert, S
Jarvelin, MR
Balkau, B
Scott, D
Froguel, P
Vaxillaire, M
Vasseur-Cognet, M
ContributionContributors NameEmailPitt UsernameORCID
Date: 14 May 2012
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 7
Number: 5
DOI or Unique Handle: 10.1371/journal.pone.0035810
Schools and Programs: School of Medicine > Medicine
Refereed: Yes
Other ID: NLM PMC3351448
PubMed Central ID: PMC3351448
PubMed ID: 22606236
Date Deposited: 29 Oct 2012 15:28
Last Modified: 04 Feb 2019 15:58


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