The impact of pro-inflammatory cytokines on the ß-cell regulatory landscape provides insights into the genetics of type 1 diabtes [UMI-4C]

Early stages of type 1 diabetes (T1D) are characterized by local autoimmune inflammation and progressive loss of insulin-producing pancreatic ß cells. We show here that exposure to pro-inflammatory cytokines unmasks a striking plasticity of the ß-cell regulatory landscape. We expand the repertoire of human islet regulatory elements by mapping stimulus-responsive enhancers linked to changes in the ß-cell transcriptome, proteome and 3D chromatin structure. Our data indicates that the ß 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 ß cells. Our study illustrates how ß cells respond to a pro-inflammatory environment and implicate a role for stimulus-response islet enhancers in T1D. Overall design: UMI-4C assays performed in control and pro-inflammatory cytokine-treated human pancreatic islets from non-diabetic cadaveric donors.