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Nat Genet. 2019 Nov;51(11):1588-1595. doi: 10.1038/s41588-019-0524-6. Epub 2019 Nov 1.

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

Author information

1
Endocrine Regulatory Genomics Laboratory, Germans Trias i Pujol University Hospital and Research Institute, Badalona, Spain.
2
Center for Diabetes Research and Welbio, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
3
Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
4
JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
5
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
6
Diabetes Research Institute, San Raffaele Scientific Institute, Milan, Italy.
7
Josep Carreras Leukaemia Research Institute, Barcelona, Spain.
8
Centro de Investigación Biomédica en Red Cáncer, Madrid, Spain.
9
Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.
10
Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.
11
Endocrine Regulatory Genomics Laboratory, Germans Trias i Pujol University Hospital and Research Institute, Badalona, Spain. lpasquali@igtp.cat.
12
Josep Carreras Leukaemia Research Institute, Barcelona, Spain. lpasquali@igtp.cat.
13
CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain. lpasquali@igtp.cat.

Abstract

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.

PMID:
31676868
DOI:
10.1038/s41588-019-0524-6

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