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Pancreatic islet chromatin accessibility and conformation reveals distal enhancer networks of type 2 diabetes risk

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Item Type:Article
Title:Pancreatic islet chromatin accessibility and conformation reveals distal enhancer networks of type 2 diabetes risk
Creators Name:Greenwald, W.W. and Chiou, J. and Yan, J. and Qiu, Y. and Dai, N. and Wang, A. and Nariai, N. and Aylward, A. and Han, J.Y. and Kadakia, N. and Regue, L. and Okino, M.L. and Drees, F. and Kramer, D. and Vinckier, N. and Minichiello, L. and Gorkin, D. and Avruch, J. and Frazer, K.A. and Sander, M. and Ren, B. and Gaulton, K.J.
Abstract:Genetic variants affecting pancreatic islet enhancers are central to T2D risk, but the gene targets of islet enhancer activity are largely unknown. We generate a high-resolution map of islet chromatin loops using Hi-C assays in three islet samples and use loops to annotate target genes of islet enhancers defined using ATAC-seq and published ChIP-seq data. We identify candidate target genes for thousands of islet enhancers, and find that enhancer looping is correlated with islet-specific gene expression. We fine-map T2D risk variants affecting islet enhancers, and find that candidate target genes of these variants defined using chromatin looping and eQTL mapping are enriched in protein transport and secretion pathways. At IGF2BP2, a fine-mapped T2D variant reduces islet enhancer activity and IGF2BP2 expression, and conditional inactivation of IGF2BP2 in mouse islets impairs glucose-stimulated insulin secretion. Our findings provide a resource for studying islet enhancer function and identifying genes involved in T2D risk.
Keywords:Cell Nucleus, Chromatin, Chromatin Assembly and Disassembly, Gene Expression Profiling, Gene Regulatory Networks, Genetic Enhancer Elements, Genetic Predisposition to Disease, Glucose, Inbred C57BL Mice, Insulin, Islets of Langerhans, Knockout Mice, Molecular Conformation, Quantitative Trait Loci, RNA-Binding Proteins, Type 2 Diabetes Mellitus, Animals, Mice
Source:Nature Communications
Publisher:Nature Publishing Group
Page Range:2078
Date:7 May 2019
Official Publication:https://doi.org/10.1038/s41467-019-09975-4
PubMed:View item in PubMed

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