Type 1 Diabetes Risk Genes Mediate Pancreatic Beta Cell Survival in Response to Proinflammatory Cytokines

Overview

Journal Cell Genom

Date 2023 Feb 13

PMID 36778047

Authors

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

Affiliations

Soon will be listed here.

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 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 , which promoted survival in cytokine exposure. Our findings reveal processes and genes acting in beta cells during inflammation that modulate T1D risk.

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References

Padgett L, Broniowska K, Hansen P, Corbett J, Tse H . The role of reactive oxygen species and proinflammatory cytokines in type 1 diabetes pathogenesis. Ann N Y Acad Sci. 2013; 1281:16-35. PMC: 3715103. DOI: 10.1111/j.1749-6632.2012.06826.x. View

Love M, Huber W, Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014; 15(12):550. PMC: 4302049. DOI: 10.1186/s13059-014-0550-8. View

Gurzov E, Barthson J, Marhfour I, Ortis F, Naamane N, Igoillo-Esteve M . Pancreatic β-cells activate a JunB/ATF3-dependent survival pathway during inflammation. Oncogene. 2011; 31(13):1723-32. DOI: 10.1038/onc.2011.353. View

Juric I, Yu M, Abnousi A, Raviram R, Fang R, Zhao Y . MAPS: Model-based analysis of long-range chromatin interactions from PLAC-seq and HiChIP experiments. PLoS Comput Biol. 2019; 15(4):e1006982. PMC: 6483256. DOI: 10.1371/journal.pcbi.1006982. View

Rosselot C, Baumel-Alterzon S, Li Y, Brill G, Lambertini L, Katz L . The many lives of Myc in the pancreatic β-cell. J Biol Chem. 2020; 296:100122. PMC: 7949031. DOI: 10.1074/jbc.REV120.011149. View

Pliner H, Packer J, McFaline-Figueroa J, Cusanovich D, Daza R, Aghamirzaie D . Cicero Predicts cis-Regulatory DNA Interactions from Single-Cell Chromatin Accessibility Data. Mol Cell. 2018; 71(5):858-871.e8. PMC: 6582963. DOI: 10.1016/j.molcel.2018.06.044. View

Soleimanpour S, Gupta A, Bakay M, Ferrari A, Groff D, Fadista J . The diabetes susceptibility gene Clec16a regulates mitophagy. Cell. 2014; 157(7):1577-90. PMC: 4184276. DOI: 10.1016/j.cell.2014.05.016. View

Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25(14):1754-60. PMC: 2705234. DOI: 10.1093/bioinformatics/btp324. View

Vinuela A, Varshney A, van de Bunt M, Prasad R, Asplund O, Bennett A . Genetic variant effects on gene expression in human pancreatic islets and their implications for T2D. Nat Commun. 2020; 11(1):4912. PMC: 7528108. DOI: 10.1038/s41467-020-18581-8. View

10.

Xu H, Luo X, Qian J, Pang X, Song J, Qian G . FastUniq: a fast de novo duplicates removal tool for paired short reads. PLoS One. 2013; 7(12):e52249. PMC: 3527383. DOI: 10.1371/journal.pone.0052249. View

11.

Kowluru A . Oxidative Stress in Cytokine-Induced Dysfunction of the Pancreatic Beta Cell: Known Knowns and Known Unknowns. Metabolites. 2020; 10(12). PMC: 7759861. DOI: 10.3390/metabo10120480. View

12.

Chiou J, Zeng C, Cheng Z, Han J, Schlichting M, Miller M . Single-cell chromatin accessibility identifies pancreatic islet cell type- and state-specific regulatory programs of diabetes risk. Nat Genet. 2021; 53(4):455-466. PMC: 9037575. DOI: 10.1038/s41588-021-00823-0. View

13.

Sharma R, Alonso L . Lipotoxicity in the pancreatic beta cell: not just survival and function, but proliferation as well?. Curr Diab Rep. 2014; 14(6):492. PMC: 4063119. DOI: 10.1007/s11892-014-0492-2. View

14.

Liao Y, Smyth G, Shi W . featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2013; 30(7):923-30. DOI: 10.1093/bioinformatics/btt656. View

15.

Machanick P, Bailey T . MEME-ChIP: motif analysis of large DNA datasets. Bioinformatics. 2011; 27(12):1696-7. PMC: 3106185. DOI: 10.1093/bioinformatics/btr189. View

16.

Gille J, Joenje H . Cell culture models for oxidative stress: superoxide and hydrogen peroxide versus normobaric hyperoxia. Mutat Res. 1992; 275(3-6):405-14. DOI: 10.1016/0921-8734(92)90043-o. View

17.

Atkinson M . The pathogenesis and natural history of type 1 diabetes. Cold Spring Harb Perspect Med. 2012; 2(11). PMC: 3543105. DOI: 10.1101/cshperspect.a007641. View

18.

Ramirez F, Ryan D, Gruning B, Bhardwaj V, Kilpert F, Richter A . deepTools2: a next generation web server for deep-sequencing data analysis. Nucleic Acids Res. 2016; 44(W1):W160-5. PMC: 4987876. DOI: 10.1093/nar/gkw257. View

19.

Lawlor N, Marquez E, Orchard P, Narisu N, Shamim M, Thibodeau A . Multiomic Profiling Identifies cis-Regulatory Networks Underlying Human Pancreatic β Cell Identity and Function. Cell Rep. 2019; 26(3):788-801.e6. PMC: 6389269. DOI: 10.1016/j.celrep.2018.12.083. View

20.

Keller M, Paul P, Rabaglia M, Stapleton D, Schueler K, Broman A . The Transcription Factor Nfatc2 Regulates β-Cell Proliferation and Genes Associated with Type 2 Diabetes in Mouse and Human Islets. PLoS Genet. 2016; 12(12):e1006466. PMC: 5147809. DOI: 10.1371/journal.pgen.1006466. View