Ramos-Rodríguez, MireiaRaurell Vila, HelenaColli, Maikel LuisAlvelos, Maria InêsSubirana-Granés, MarcJuan-Mateu, JonàsNorris, RichardTuratsinze, Jean-ValeryNakayasu, Ernesto S.Webb-Robertson, Bobbie-Jo M.Inshaw, Jamie R. J.Marchetti, PieroPiemonti, LorenzoEsteller, ManelTodd, John A.Metz, Thomas O.Eizirik, Décio L.Pasquali, Lorenzo2022-02-102022-02-102019Ramos-Rodríguez M, Raurell-Vila H, Colli ML, Alvelos MI, Subirana-Granés M, Juan-Mateu J, Norris R, Turatsinze JV, Nakayasu ES, Webb-Robertson BM, Inshaw JRJ, Marchetti P, Piemonti L, Esteller M, Todd JA, Metz TO, Eizirik DL, Pasquali L. The impact of proinflammatory cytokines on the β-cell regulatory landscape provides insights into the genetics of type 1 diabetes. Nat Genet. 2019;51(11):1588-95. DOI: 10.1038/s41588-019-0524-61061-4036http://hdl.handle.net/10230/52452The 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.application/pdfeng© Springer Nature Publishing AG Ramos-Rodríguez M, Raurell-Vila H, Colli ML, Alvelos MI, Subirana-Granés M, Juan-Mateu J, Norris R, Turatsinze JV, Nakayasu ES, Webb-Robertson BM, Inshaw JRJ, Marchetti P, Piemonti L, Esteller M, Todd JA, Metz TO, Eizirik DL, Pasquali L. The impact of proinflammatory cytokines on the β-cell regulatory landscape provides insights into the genetics of type 1 diabetes. Nat Genet. 2019;51(11):1588-95. DOI: 10.1038/s41588-019-0524-6 [http://dx.doi.org/10.1038/s41588-019-0524-6]info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41588-019-0524-6Endocrine system and metabolic diseasesEpigenomicsGene regulationinfo:eu-repo/semantics/openAccess