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

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.; Gaulton, K.J.

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

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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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