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Interferon-α (IFNα), a type I interferon, is expressed in the islets of type 1 diabetic individuals, and its expression and signaling are regulated by T1D genetic risk variants and viral infections associated with T1D. We presently characterize human beta cell responses to IFNα by combining ATAC-seq, RNA-seq and proteomics assays. The initial response to IFNα is characterized by chromatin remodeling, followed by changes in transcriptional and translational regulation. IFNα induces changes in alternative splicing (AS) and first exon usage, increasing the diversity of transcripts expressed by the beta cells. This, combined with changes observed on protein modification/degradation, ER stress and MHC class I, may expand antigens presented by beta cells to the immune system. Beta cells also up-regulate the checkpoint proteins PDL1 and HLA-E that may exert a protective role against the autoimmune assault. Data mining of the present multi-omics analysis identifies two compound classes that antagonize IFNα effects on human beta cells. ; This work was supported by grants from the Fonds National de la Recherche Scientifique (FNRS), Welbio CR-2015A-06 and CR-2019C-04, Belgium; the Horizon 2020 Program, T2Dsystems (GA667191); the National Institutes of Health, NIH-NIDDK-HIRN Consortium 1UC4DK104166-01 and Innovate2CureType1 - Dutch Diabetes Research Fundation (DDRF). D.L.E. and P.M. have received funding from the Innovative Medicines Initiative 2 Joint Undertaking under Grant Agreement No. 115797 (INNODIA). This Joint Undertaking receives support from the Union's Horizon 2020 research and innovation programme and "EFPIA", "JDRF" and "The Leona M. and Harry B. Helmsley Charitable Trust". The DiViD study is funded by The South-Eastern Norway Regional Health Authority (grant to K.D.-J.), the Novo Nordisk Foundation (grant to K.D.-J.), and through the PEVNET (Persistent Virus Infection in Diabetes Network) Study Group funded by the European Union's Seventh Framework Programme (FP7/2007-2013) under grant Agreement Number 261441 PEVNET. Additional support was from a JDRF Career Development Award (5-CDA-2014-221-A-N) to S.J.R., a JDRF research grant awarded to the network of Pancreatic Organ Donors – Virus (nPOD-V) consortium (JDRF 25-2012-516); an MRC Project Grant MR/P010695/1 awarded to S.J.R. and N.G.M., a studentship grant from the Norman Family Trust (to S.J.R. and N.G.M.), a Spanish Ministry of Economy and Competiveness (SAF2017-86242-R to L.P.) and Marató TV3 (201624.10 to L.P.). L.P. is a recipient of a Ramon y Cajal contract from the Spanish Ministry of Economy and Competitiveness (RYC-2013-12864) and M.R. is supported by an FI Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR) PhD fellowship.

The early stages of type 1 diabetes (T1D) are characterized by local autoimmune inflammation and progressive loss of insulin-producing pancreatic β cells. Here we show that exposure to proinflammatory cytokines reveals a marked plasticity of the β-cell regulatory landscape. We expand the repertoire of human islet regulatory elements by mapping stimulus-responsive enhancers linked to changes in the β-cell transcriptome, proteome and three-dimensional chromatin structure. Our data indicate that the β-cell response to cytokines is mediated by the induction of new regulatory regions as well as the activation of primed regulatory elements prebound by islet-specific transcription factors. We find that T1D-associated loci are enriched with newly mapped cis-regulatory regions and identify T1D-associated variants disrupting cytokine-responsive enhancer activity in human β cells. Our study illustrates how β cells respond to a proinflammatory environment and implicate a role for stimulus response islet enhancers in T1D. ; L.Pasquali was supported by grants from the Spanish Ministry of Economy and Competitiveness (nos. BFU2014-58150-R and SAF2017-86242-R), Marató TV3 (no. 201624.10) and a young investigator award from the Spanish Society of Diabetes (Ayuda SED a Proyectos de Investigación, no. 2017-SED). L.Pasquali is a recipient of a Ramon y Cajal contract from the Spanish Ministry of Economy and Competitiveness (no. RYC-2013-12864). The Pasquali lab is further supported by Instituto de Salud Carlos III (no. PIE16/00011). M.R. is supported by an FI Agència de Gestió d'Ajuts Universitaris i de Recerca PhD fellowship (no. 2019FI_B100203). J.J. was supported by a Marie Skłodowska-Curie Actions fellowship grant from the Horizons 2020 European Union (EU) Programme (project no. 660449). M.I.A. was supported by a FRIA fellowship from the Fonds de la Recherche Scientifique (FNRS) (no. 26410496). Human islets were provided through the European Consortium for Islet Transplantation distribution program for basic research supported by JDRF (no. 31-2008-416). D.L.E. was supported by the Walloon Region through the FRFS-WELBIO Fund for Strategic Fundamental research (no. CR-2015A-06s and CR-2019C-04) and by grants from the Fonds National de la Recherche Scientifique (no. T003613F), the Horizon 2020 Programme (project T2Dsystems, no. GA667191), Brussels Capital Region Innoviris (project DiaType, no. 2017-PFS-24), Dutch Diabetes Research Fundation (project Innovate2CureType1, DDRF; no. 2018.10.002) and the Innovative Medicines Initiative 2 Joint Undertaking (project INNODIA, no. 115797). This Innovative Medicines Initiative 2 Joint Undertaking receives support from the EU's Horizon 2020 Research and Innovation Programme and European Federation of Pharmaceutical Industries and Associations, JDRF and the Leona M. and Harry B. Helmsley Charitable Trust (project INNODIA, no. 115797). T.O.M. and D.L.E. were supported by a grant from the National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases-Human Islet Research Network Consortium (no. 1UC4DK104166-01). Part of the work was performed at the Environmental Molecular Sciences Laboratory, a US Department of Energy national scientific user facility located at Pacific Northwest National Laboratory. Battelle operates the Pacific Northwest National Laboratory for the Department of Energy (contract no. DE-AC05-76RLO01830).