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| Item Type: | Article |
|---|---|
| Title: | Type 1 diabetes risk genes mediate pancreatic beta cell survival in response to proinflammatory cytokines |
| Creators Name: | Benaglio, P., Zhu, H., Okino, M.L., Yan, J., Elgamal, R., Nariai, N., Beebe, E., Korgaonkar, K., Qiu, Y., Donovan, M.K.R., Chiou, J., Wang, G., Newsome, J., Kaur, J., Miller, M., Preissl, S., Corban, S., Aylward, A., Taipale, J., Ren, B., Frazer, K.A., Sander, M. and Gaulton, K.J. |
| 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. |
| Keywords: | Type 1 Diabetes, Beta Cell, Proinflammatory Cytokines, Functional Genomics, Accessible Chromatin, 3D Chromatin Interactions, Gene Expression, Human Genetics, CRISPR Screen, High-Throughput Reporter Assay |
| Source: | Cell Genomics |
| ISSN: | 2666-979X |
| Publisher: | Cell Press |
| Volume: | 2 |
| Number: | 12 |
| Page Range: | 100214 |
| Date: | 14 December 2022 |
| Official Publication: | https://doi.org/10.1016/j.xgen.2022.100214 |
| PubMed: | View item in PubMed |
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