par Ramos-Rodríguez, Mireia;Raurell-Vila, Helena;Colli, Maikel Luis ;Alvelos, Maria Inês;Subirana-Granés, Marc;Juan-Mateu, Jonàs;Norris, Richard;Turatsinze, Jean Valéry ;Nakayasu, Ernesto Satoshi;Webb-Robertson, Bobbie-Jo M.;Inshaw, Jamie J.R.J.;Marchetti, Piero;Piemonti, Lorenzo;Esteller, Manel;Todd, John A;Metz, Thomas O.;Eizirik, Decio L. ;Pasquali, Lorenzo
Référence Nature genetics, 51, 11, page (1588-1595)
Publication Publié, 2019-11-01
Référence Nature genetics, 51, 11, page (1588-1595)
Publication Publié, 2019-11-01
Article révisé par les pairs
Résumé : | 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. |