We have updated our privacy policy. If you have any question, contact us at privacy@scicrunch.org. Dismiss and don't show again

Searching across hundreds of databases

Our searching services are busy right now. Your search will reload in five seconds.

Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

Alterations in TCF7L2 expression define its role as a key regulator of glucose metabolism.

Genome research | Sep 2, 2011

Genome-wide association studies (GWAS) have consistently implicated noncoding variation within the TCF7L2 locus with type 2 diabetes (T2D) risk. While this locus represents the strongest genetic determinant for T2D risk in humans, it remains unclear how these noncoding variants affect disease etiology. To test the hypothesis that the T2D-associated interval harbors cis-regulatory elements controlling TCF7L2 expression, we conducted in vivo transgenic reporter assays to characterize the TCF7L2 regulatory landscape. We found that the 92-kb genomic interval associated with T2D harbors long-range enhancers regulating various aspects of the spatial-temporal expression patterns of TCF7L2, including expression in tissues involved in the control of glucose homeostasis. By selectively deleting this interval, we establish a critical role for these enhancers in robust TCF7L2 expression. To further determine whether variation in Tcf7l2 expression may lead to diabetes, we developed a Tcf7l2 copy-number allelic series in mice. We show that a null Tcf7l2 allele leads, in a dose-dependent manner, to lower glycemic profiles. Tcf7l2 null mice also display enhanced glucose tolerance coupled to significantly lowered insulin levels, suggesting that these mice are protected against T2D. Confirming these observations, transgenic mice harboring multiple Tcf7l2 copies and overexpressing this gene display reciprocal phenotypes, including glucose intolerance. These results directly demonstrate that Tcf7l2 plays a role in regulating glucose tolerance, suggesting that overexpression of this gene is associated with increased risk of T2D. These data highlight the role of enhancer elements as mediators of T2D risk in humans, strengthening the evidence that variation in cis-regulatory elements may be a paradigm for genetic predispositions to common disease.

Pubmed ID: 21673050 RIS Download

Mesh terms: Alleles | Animals | Base Sequence | Blood Glucose | Chromosomes, Artificial, Bacterial | Diabetes Mellitus, Type 2 | Enhancer Elements, Genetic | Female | Gene Expression | Gene Expression Regulation | Gene Order | Genetic Predisposition to Disease | Genotype | Glucose | Humans | Male | Metabolic Networks and Pathways | Mice | Mice, Knockout | Phenotype | Transcription Factor 7-Like 2 Protein

Research resources used in this publication

None found

Research tools detected in this publication

None found

Data used in this publication

None found

Associated grants

  • Agency: NHGRI NIH HHS, Id: R01 HG004428
  • Agency: NIDDK NIH HHS, Id: DK-20595
  • Agency: NIDDK NIH HHS, Id: DK-078871
  • Agency: NHGRI NIH HHS, Id: HG004428
  • Agency: NIGMS NIH HHS, Id: T32 GM007197
  • Agency: NIDDK NIH HHS, Id: R21 DK078871
  • Agency: NIDDK NIH HHS, Id: P30 DK020595
  • Agency: NIDDK NIH HHS, Id: P60 DK020595

Mouse Genome Informatics (Data, Gene Annotation)

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.

We have not found any resources mentioned in this publication.