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Type 1 diabetes risk genes mediate pancreatic beta cell survival in response to proinflammatory cytokines
Authors
Anthony Aylward
Elisha Beebe
+21 more
Paola Benaglio
Joshua Chiou
Sierra Corban
Margaret K.R. Donovan
Ruth Elgamal
Kelly A. Frazer
Kyle J. Gaulton
Jaspreet Kaur
Katha Korgaonkar
Michael Miller
Naoki Nariai
Jacklyn Newsome
Mei Lin Okino
Sebastian Preissl
Yunjiang Qiu
Bing Ren
Maike Sander
Jussi Taipale
Gaowei Wang
Jian Yan
Han Zhu
Publication date
1 December 2022
Publisher
Doi
Cite
Abstract
Publisher Copyright: © 2022We combined functional genomics and human genetics to investigate processes that affect type 1 diabetes (T1D) risk by mediating beta cell survival in response to proinflammatory cytokines. We mapped 38,931 cytokine-responsive candidate cis-regulatory elements (cCREs) in beta cells using ATAC-seq and snATAC-seq and linked them to target genes using co-accessibility and HiChIP. Using a genome-wide CRISPR screen in EndoC-βH1 cells, we identified 867 genes affecting cytokine-induced survival, and genes promoting survival and up-regulated in cytokines were enriched at T1D risk loci. Using SNP-SELEX, we identified 2,229 variants in cytokine-responsive cCREs altering transcription factor (TF) binding, and variants altering binding of TFs regulating stress, inflammation, and apoptosis were enriched for T1D risk. At the 16p13 locus, a fine-mapped T1D variant altering TF binding in a cytokine-induced cCRE interacted with SOCS1, which promoted survival in cytokine exposure. Our findings reveal processes and genes acting in beta cells during inflammation that modulate T1D risk.Peer reviewe
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