Title: Investigation of noncoding variation in human pancreatic islets and their developmental precursors. The goal of this research project is to understand the role of genetic variation in non- protein coding, regulatory regions of the genome in human pancreatic islet function and dysfunction. Insulin-secreting cells in the islet are responsible for maintaining normal blood glucose levels. Type 2 diabetes (T2D) results from progressive failure of these cells to secrete insulin in the face of increasing blood glucose levels and is the cause of substantial morbidity and mortality in the United States and worldwide. Development of T2D involves complex interactions between an individual's genes and environment. Genetic association studies have identified approximately 40 regions in the genome that confer risk of developing T2D. The majority of these regions does not contain coding sequence variants, but instead contains non-coding variants. This project uses genome- wide chromatin profiling to identify the critical regulatory elements that contribute to T2D by determining which of the candidate regulatory regions function as enhancers, silencers, or insulators in human islets (Specific Aim 1) and which elements contain variants that alter gene expression in adult human islets (Specific Aim 2) or in pancreatic precursor cells (Specific Aim 3). Completion of these aims will provide detailed functional annotation of enhancer, silencer, and insulator elements, identify key regulatory element-promoter interactions, and identify how T2D-associated and other variants alter their function in human pancreatic precursor or mature islet cells.
Type 2 diabetes (T2D) afflicts 270-285 million people worldwide and is a major risk factor for subsequent vascular and neurologic morbidity including cardiovascular disease, kidney failure, blindness, and peripheral neuropathy. T2D is the consequence of dysfunction and failure of pancreatic islet beta cells in the context of increased insulin resistance and involves complex interactions between an individual's genes and environment. The goal of this research project is to understand the role(s) of regulatory, non-protein coding regions in human pancreatic islet dysfunction and genetic risk of T2D.
|Khetan, Shubham; Kursawe, Romy; Youn, Ahrim et al. (2018) Type 2 Diabetes-Associated Genetic Variants Regulate Chromatin Accessibility in Human Islets. Diabetes 67:2466-2477|
|Kycia, Ina; Wolford, Brooke N; Huyghe, Jeroen R et al. (2018) A Common Type 2 Diabetes Risk Variant Potentiates Activity of an Evolutionarily Conserved Islet Stretch Enhancer and Increases C2CD4A and C2CD4B Expression. Am J Hum Genet 102:620-635|
|Varshney, Arushi; Scott, Laura J; Welch, Ryan P et al. (2017) Genetic regulatory signatures underlying islet gene expression and type 2 diabetes. Proc Natl Acad Sci U S A 114:2301-2306|
|Lawlor, Nathan; Khetan, Shubham; Ucar, Duygu et al. (2017) Genomics of Islet (Dys)function and Type 2 Diabetes. Trends Genet 33:244-255|
|Lawlor, Nathan; Youn, Ahrim; Kursawe, Romy et al. (2017) Alpha TC1 and Beta-TC-6 genomic profiling uncovers both shared and distinct transcriptional regulatory features with their primary islet counterparts. Sci Rep 7:11959|
|Roman, Tamara S; Cannon, Maren E; Vadlamudi, Swarooparani et al. (2017) A Type 2 Diabetes-Associated Functional Regulatory Variant in a Pancreatic Islet Enhancer at the ADCY5 Locus. Diabetes 66:2521-2530|
|Fuchsberger, Christian (see original citation for additional authors) (2016) The genetic architecture of type 2 diabetes. Nature 536:41-47|
|Stitzel, Michael L; Kycia, Ina; Kursawe, Romy et al. (2015) Transcriptional Regulation of the Pancreatic Islet: Implications for Islet Function. Curr Diab Rep 15:66|
|Majithia, Amit R; Flannick, Jason; Shahinian, Peter et al. (2014) Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes. Proc Natl Acad Sci U S A 111:13127-32|
|Parker, Stephen C J; Stitzel, Michael L; Taylor, D Leland et al. (2013) Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants. Proc Natl Acad Sci U S A 110:17921-6|
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