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

Ramos-Rodríguez, Mireia; Raurell Vila, Helena; Colli, Maikel Luis; Alvelos, Maria Inês; Subirana-Granés, Marc; Juan-Mateu, Jonàs; Norris, Richard; Turatsinze, Jean-Valery; Nakayasu, Ernesto S.; Webb-Robertson, Bobbie-Jo M.; Inshaw, Jamie R. J.; Marchetti, Piero; Piemonti, Lorenzo; Esteller, Manel; Todd, John A.; Metz, Thomas O.; Eizirik, Décio L.; Pasquali, Lorenzo

doi:http://dx.doi.org/10.1038/s41588-019-0524-6

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

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

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.