Supporting data for: Type 1 diabetes risk genes mediate pancreatic beta cell survival in response to proinflammatory cytokines

SUMMARY OF THE STUDY

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.

DESCRIPTION OF FILES:

• Supplementary Data 1. List of islet cCREs annotated with cell type and cytokine response  - also in GSE205853
• Supplementary Data 2. Coaccessible sites in untreated beta cells and promoter annotations - also in GSE205853
• Supplementary Data 3. Coaccessible sites in cytokine-treated beta cells and promoter annotations - also in GSE205853
• Supplementary Data 4. Coaccessible sites in cytokine treated and untreated beta cells and promoter annotations - also in GSE205853
• Supplementary Data 5. Chromatin interactions in EndoC-BH1 cells - also in GSE205853
• Supplementary Data 6. Variants selected for SNP-SELEX assay 
• Supplementary Data 7. Variants with TF binding and allelic binding results from SNP-SELEX
• Supplementary Data 8. snATAC-seq barcodes and metadata - also in GSE205853
• Supplementary Data 9. CRISPR-KO screen results - also in GSE205853
• Supplementary Data 10. Bulk ATAC-seq count matrix - also in GSE205853
• Supplementary Data 11. Bulk RNA-seq count matrix - also in GSE205853
• Supplementary Data 12. Alpha cells snATAC-seq count matrix - also in GSE205853
• Supplementary Data 13. Acinar cells snATAC-seq count matrix - also in GSE205853
• Supplementary Data 14. Beta cells snATAC-seq count matrix - also in GSE205853
• Supplementary Data 15. Stellate cells snATAC-seq count matrix - also in GSE205853
• Supplementary Data 16. Endothelial cells snATAC-seq count matrix - also in GSE205853
• Supplementary Data 17. Delta cells snATAC-seq count matrix - also in GSE205853
• Supplementary Data 18. Luciferase assay rs10483809
• Supplementary Data 19. SOCS1 knockdown qPCR results
• Supplementary Data 20. SOCS1 knockdown Apotracker (flow-cytometry)results

Raw data deposited at GEO, accessions GSE205853 and GSE118725.

Please refer to publication and GEO for details on methods.