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

ABSTRACT: The early stages of type 1 diabetes (T1D) are characterized by local autoimmune inflammation and progressive loss of insulin-producing pancreatic ? cells. Here we show that exposure to proinflammatory cytokines reveals a marked plasticity of the ?-cell regulatory landscape. We expand the repertoire of human islet regulatory elements by mapping stimulus-responsive enhancers linked to changes in the ?-cell transcriptome, proteome and three-dimensional chromatin structure. Our data indicate that the ?-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 ? cells. Our study illustrates how ? cells respond to a proinflammatory environment and implicate a role for stimulus response islet enhancers in T1D.

SUBMITTER: Ramos-Rodriguez M 

PROVIDER: S-EPMC7040466 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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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 th  ...[more]

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