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

Mireia Ramos-Rodríguez, Helena Raurell-Vila, Maikel L. Colli, Maria Inês Alvelos, Marc Subirana-Granés, Jonàs Juan-Mateu, Richard Norris, Jean-Valery Turatsinze, Ernesto S. Nakayasu, Bobbie-Jo M. Webb-Robertson, Jamie R. J. Inshaw, Piero Marchetti, Lorenzo Piemonti, Manel Esteller, John A. Todd, Thomas O. Metz, Décio L. Eizirik & Lorenzo Pasquali.
Nature Genetics. 2019-11-01;51:1588–1595.
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.
Consortium data used in this publication
GSE123404 (ATAC-seq); GSE133135 (H3K27ac data); GSE137136 (RNA-seq)