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

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

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Savic, Daniel Ye, Honggang Aneas, Ivy Park, Soo-Young Bell, Graeme I. Nobrega, Marcelo A.
Description	Country affiliation: United States Author Affiliation: Savic D ( Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA. dsavic@uchicago.edu)
Abstract	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.
File Format	HTM / HTML
ISSN	10889051
e-ISSN	15495469
DOI	10.1101/gr.123745.111
Journal	Genome Research
Issue Number	9
Volume Number	21
Language	English
Publisher	Cold Spring Harbor Laboratory Press
Publisher Date	2011-09-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Genetics Discipline Genomics Gene Expression Regulation Glucose Metabolism Transcription Factor 7-like 2 Protein Genetics Alleles Animals Blood Glucose Chromosomes, Artificial, Bacterial Diabetes Mellitus, Type 2 Enhancer Elements, Genetic Gene Expression Gene Order Genetic Predisposition To Disease Genotype Metabolic Networks And Pathways Mice Mice, Knockout Phenotype Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Genetics Genetics (clinical)

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