The response of beta cells to inflammatory cytokines contributes to type 1 diabetes (T1D) risk, but the specific genes that underlie this response and mediate beta cell survival remain largely unknown. In this study we used a suite of functional genomics assays combined with human genetics, to map cis-regulatory programs in beta cells and to identify T1D genes that affect beta cell survival upon exposure to the pro-inflammatory cytokines IL1β, IFNγ and TNFα. We mapped 38,931 cytokine-responsive candidate cis­­ -regulatory elements (cCREs) active in beta cells using ATAC-seq and single nuclear ATAC-seq (snATAC-seq) , and linked cytokine-responsive beta cell cCREs to putative target genes using single cell co-accessibility and HiChIP. We performed a genome-wide pooled CRISPR loss-of-function screen in EndoC-βH1 cells, which identified 867 genes affecting cytokine-induced beta cell loss. Genes that promoted beta cell survival and had up-regulated expression in cytokine exposure were specifically enriched at T1D loci, and these genes were preferentially involved in inhibiting inflammatory response, ubiquitin-mediated proteolysis, mitophagy and autophagy. We identified 2,229 variants in cytokine-responsive beta cell cCREs altering transcription factor (TF) binding using high-throughput SNP-SELEX, and variants altering binding of TF families regulating stress, inflammation and apoptosis were broadly enriched for T1D association. Finally, through integration with genetic fine mapping, we identified T1D risk variants regulating beta cell survival in cytokine exposure. At the 16p13 locus, a T1D variant affected TF binding in a cytokine-induced beta cell cCRE that physically interacted with the SOCS1 promoter, and increased SOCS1 activity promoted beta cell survival in cytokine exposure. Together our findings reveal processes and genes acting in beta cells during cytokine exposure that intrinsically modulate risk of T1D.

Disclosure

P.Benaglio: None. M.Donovan: None. J.Chiou: Employee; Pfizer Inc. J.M.Newsome ashmus: None. J.Kaur: None. S.Corban: None. B.Ren: Stock/Shareholder; Arima Genomics, Epigenome Technologies. K.Frazer: n/a. M.Sander: None. K.J.Gaulton: Consultant; Genentech, Inc., Stock/Shareholder; Neurocrine Biosciences, Inc., Vertex Pharmaceuticals Incorporated. H.Zhu: None. M.Okino: None. J.Yan: None. R.Elgamal: None. N.Nariai: None. E.Beebe: None. K.Korgaonkar: None. Y.Qiu: None.

Funding

NIH DK122607

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