Type 1 diabetes risk genes mediate pancreatic beta cell survival in response to proinflammatory cytokines
Authors
- P. Benaglio
- H. Zhu
- M.L. Okino
- J. Yan
- R. Elgamal
- N. Nariai
- E. Beebe
- K. Korgaonkar
- Y. Qiu
- M.K.R. Donovan
- J. Chiou
- G. Wang
- J. Newsome
- J. Kaur
- M. Miller
- S. Preissl
- S. Corban
- A. Aylward
- J. Taipale
- B. Ren
- K.A. Frazer
- M. Sander
- K.J. Gaulton
Journal
- Cell Genomics
Citation
- Cell Genom 2 (12): 100214
Abstract
We 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 cyto- kine-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-bH1 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 pro- moted survival in cytokine exposure. Our findings reveal processes and genes acting in beta cells during inflammation that modulate T1D risk.