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The impact of proinflammatory cytokines on the β-cell regulatory landscape provides insights into the genetics of type 1 diabetes
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The impact of proinflammatory cytokines on the β-cell regulatory landscape provides insights into the genetics of type 1 diabetes
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Journal Article
The impact of proinflammatory cytokines on the β-cell regulatory landscape provides insights into the genetics of type 1 diabetes
2019
Overview
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.
Cytokine-induced regulatory changes in human pancreatic islets illustrate the β-cell chromatin dynamics in response to a proinflammatory environment and implicate a role for islet enhancers in type 1 diabetes.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ 38
/ 45
/ 45/15
/ 45/43
/ 45/70
/ 45/91
/ 82/80
/ Animal Genetics and Genomics
/ Biomedical and Life Sciences
/ Diabetes
/ Diabetes mellitus (insulin dependent)
/ Diabetes Mellitus, Type 1 - drug therapy
/ Diabetes Mellitus, Type 1 - genetics
/ Diabetes Mellitus, Type 1 - pathology
/ Gene Expression Regulation - drug effects
/ Genetics
/ Genome-Wide Association Study
/ Genomes
/ Humans
/ Insulin
/ Insulin-Secreting Cells - drug effects
/ Insulin-Secreting Cells - metabolism
/ Insulin-Secreting Cells - pathology
/ Mapping
/ Pancreas
/ Proteins
/ Software
