Type 1 diabetes risk genes mediate pancreatic beta cell survival in response to proinflammatory cytokines

Cell Genom. 2022 Nov 11;2(12):100214. doi: 10.1016/j.xgen.2022.100214. eCollection 2022 Dec 14.


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 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.

Keywords: 3D chromatin interactions; CRISPR screen; accessible chromatin; beta cell; functional genomics; gene expression; high-throughput reporter assay; human genetics; proinflammatory cytokines; type 1 diabetes.