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

William W. Greenwald, Joshua Chiou, Jian Yan, Yunjiang Qiu, Ning Dai, Allen Wang, Naoki Nariai, Anthony Aylward, Jee Yun Han, Nikita Kadakia, Laura Regue, Mei-Lin Okino, Frauke Drees, Dana Kramer, Nicholas Vinckier, Liliana Minichiello, David Gorkin, Joseph Avruch, Kelly A. Frazer, Maike Sander, Bing Ren and Kyle J. Gaulton ()
Additional contact information
William W. Greenwald: Bioinformatics and Systems Biology Graduate Program
Joshua Chiou: Biomedical Sciences Graduate Program
Jian Yan: Ludwig Institute for Cancer Research
Yunjiang Qiu: Bioinformatics and Systems Biology Graduate Program
Ning Dai: Harvard University
Allen Wang: Department of Pediatrics
Naoki Nariai: Department of Pediatrics
Anthony Aylward: Bioinformatics and Systems Biology Graduate Program
Jee Yun Han: Center for Epigenomics
Nikita Kadakia: Department of Pediatrics
Laura Regue: Harvard University
Mei-Lin Okino: Department of Pediatrics
Frauke Drees: Department of Pediatrics
Dana Kramer: Mouse Biology Unit
Nicholas Vinckier: Department of Pediatrics
Liliana Minichiello: Mouse Biology Unit
David Gorkin: Center for Epigenomics
Joseph Avruch: Harvard University
Kelly A. Frazer: Department of Pediatrics
Maike Sander: Department of Pediatrics
Bing Ren: Ludwig Institute for Cancer Research
Kyle J. Gaulton: Department of Pediatrics

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09975-4

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