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

Journal article

Early stages of type 1 diabetes (T1D) are characterized by local autoimmune inflammation and progressive loss of insulin-producing pancreatic β cells. We show here that exposure to pro-inflammatory cytokines unmasks 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 3D chromatin structure. Our data indicates that the β cell response to cytokines is mediated by the induction of novel regulatory regions as well as the activation of primed regulatory elements pre-bound by islet-specific transcription factors. We found that T1D associated loci are enriched of the 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 pro-inflammatory environment and implicate a role for stimulus-response islet enhancers in T1D.

Authors: Ramos-Rodríguez, M; Raurell-Vila, H; Colli, M; Alvelos, M; Subirana, M

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Springer Nature
• Journal: Nature Genetics
• Volume: 51
• Pages: 1588–1595
• Publication date: 2019-11-01
• Acceptance date: 2019-06-05
• DOI: 10.1038/s41588-019-0524-6
• EISSN: 1546-1718
• ISSN: 1061-4036
• Language: English