| Notes: | Advisor: Marcelo A. Nobrega.
Thesis (Ph.D.)--The University of Chicago, Division of the Biological Sciences, and The Pritzker School of Medicine, Department of Human Genetics, 2012.
Dissertation Abstracts International, Volume: 73-07, Section: B, page: .
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| Summary: | Genome wide association studies have consistently implicated non-coding 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 non-coding variants affect disease etiology. In addition to T2D, this region has also been associated with schizophrenia risk. To test the hypothesis that the T2D- and schizophrenia-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. A systematic two-tiered fine-mapped saturation enhancer screen was subsequently preformed on the association interval that utilized both in vitro and in vivo approaches. This strategy localized a set of long-range TCF7L2 enhancers. 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 including enhanced glucose tolerance in heterozygous null adult mice, suggesting that these mice are protected against T2D. Confirming these observations, transgenic mice harboring multiple Tcf7l2 copies and over-expressing this gene display reciprocal phenotypes, including glucose intolerance, thereby defining a predisposition to T2D in these mice. In addition to metabolic defects, alterations in Tcf7l2 expression in these animal models also led to behavioral phenotypes that are suggestive of schizophrenia. These results directly demonstrate that Tcf7l2 plays a role in regulating glucose tolerance and behavior. These data also highlight the potential role of enhancer elements as mediators of T2D and schizophrenia risk in humans, strengthening the evidence that variation in cis-regulatory elements may be a paradigm for genetic predispositions to common disease.
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