The impact of proinflammatory cytokines on the β-cell regulatory landscape provides insights into the genetics of type 1 diabetes

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• dc.contributor.author Ramos-Rodríguez, Mireia
• dc.contributor.author Raurell Vila, Helena
• dc.contributor.author Colli, Maikel Luis
• dc.contributor.author Alvelos, Maria Inês
• dc.contributor.author Subirana-Granés, Marc
• dc.contributor.author Juan-Mateu, Jonàs
• dc.contributor.author Norris, Richard
• dc.contributor.author Turatsinze, Jean-Valery
• dc.contributor.author Nakayasu, Ernesto S.
• dc.contributor.author Webb-Robertson, Bobbie-Jo M.
• dc.contributor.author Inshaw, Jamie R. J.
• dc.contributor.author Marchetti, Piero
• dc.contributor.author Piemonti, Lorenzo
• dc.contributor.author Esteller, Manel
• dc.contributor.author Todd, John A.
• dc.contributor.author Metz, Thomas O.
• dc.contributor.author Eizirik, Décio L.
• dc.contributor.author Pasquali, Lorenzo
• dc.date.accessioned 2022-02-10T06:49:08Z
• dc.date.available 2022-02-10T06:49:08Z
• dc.date.issued 2019
• dc.description.abstract 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.
• dc.description.sponsorship 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).
• dc.format.mimetype application/pdf
• dc.identifier.citation 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
• dc.identifier.doi http://dx.doi.org/10.1038/s41588-019-0524-6
• dc.identifier.issn 1061-4036
• dc.identifier.uri http://hdl.handle.net/10230/52452
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nat Genet. 2019;51(11):1588-95
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/660449
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2014-58150-R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/SAF2017-86242-R
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/115797
• dc.rights © 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]
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.keyword Endocrine system and metabolic diseases
• dc.subject.keyword Epigenomics
• dc.subject.keyword Gene regulation
• dc.title The impact of proinflammatory cytokines on the β-cell regulatory landscape provides insights into the genetics of type 1 diabetes
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion