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

Paola Benaglio; Han Zhu; Mei-Lin Okino; Jian Yan; Ruth Elgamal; Naoki Nariai; Elisha Beebe; Katha Korgaonkar; Yunjiang Qiu; Margaret K R Donovan; Joshua Chiou; Gaowei Wang; Jacklyn Newsome; Jaspreet Kaur; Michael Miller; Sebastian Preissl; Sierra Corban; Anthony Aylward; Jussi Taipale; Bing Ren; Kelly A Frazer; Maike Sander; Kyle J Gaulton

doi:10.1016/j.xgen.2022.100214

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.

Authors

Paola Benaglio¹, Han Zhu^{1

2}, Mei-Lin Okino^{1

2}, Jian Yan^{3

4

5

6}, Ruth Elgamal¹, Naoki Nariai¹, Elisha Beebe¹, Katha Korgaonkar¹, Yunjiang Qiu², Margaret K R Donovan¹, Joshua Chiou¹, Gaowei Wang^{1

2}, Jacklyn Newsome¹, Jaspreet Kaur¹, Michael Miller⁷, Sebastian Preissl⁷, Sierra Corban¹, Anthony Aylward¹, Jussi Taipale^{6

8

9}, Bing Ren^{2

3

7}, Kelly A Frazer¹, Maike Sander^{1

2}, Kyle J Gaulton¹

Affiliations

¹ Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA.
² Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
³ Ludwig Institute for Cancer Research, La Jolla, CA, USA.
⁴ School of Medicine, Northwest University, Xi'an, China.
⁵ Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China.
⁶ Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden.
⁷ Center for Epigenomics, University of California, San Diego, La Jolla, CA, USA.
⁸ Department of Biochemistry, University of Cambridge, Cambridge, UK.
⁹ Genome-Scale Biology Program, University of Helsinki, Helsinki, Finland.

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 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.

Abstract

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