期刊
NATURE GENETICS
卷 51, 期 11, 页码 1588-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41588-019-0524-6
关键词
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资金
- Spanish Ministry of Economy and Competitiveness [BFU2014-58150-R, SAF2017-86242-R, RYC-2013-12864]
- Marato TV3 [201624.10]
- Spanish Society of Diabetes (Ayuda SED a Proyectos de Investigacion) [2017-SED]
- Instituto de Salud Carlos III [PIE16/00011]
- FI Agencia de Gestio d'Ajuts Universitaris i de Recerca PhD fellowship [2019FI_B100203]
- Marie Sklodowska-Curie Actions fellowship grant from the Horizons 2020 European Union (EU) Programme [660449]
- Fonds de la Recherche Scientifique (FNRS) [26410496]
- JDRF [31-2008-416]
- Walloon Region through the FRFS-WELBIO Fund for Strategic Fundamental research [CR-2015A-06s, CR-2019C-04]
- Fonds National de la Recherche Scientifique [T003613F]
- Horizon 2020 Programme (project T2Dsystems) [GA667191]
- Brussels Capital Region Innoviris (project DiaType) [2017-PFS-24]
- Dutch Diabetes Research Fundation (project Innovate2CureType1, DDRF) [2018.10.002]
- Innovative Medicines Initiative 2 Joint Undertaking (project INNODIA) [115797]
- EU's Horizon 2020 Research and Innovation Programme
- European Federation of Pharmaceutical Industries and Associations
- JDRF
- Leona M. and Harry B. Helmsley Charitable Trust (project INNODIA) [115797]
- National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases-Human Islet Research Network Consortium [1UC4DK104166-01]
- Department of Energy [DE-AC05-76RLO01830]
- Marie Curie Actions (MSCA) [660449] Funding Source: Marie Curie Actions (MSCA)
The early stages of type 1 diabetes (T1D) are characterized by local autoimmune inflammation and progressive loss of insulin-producing pancreatic beta cells. Here we show that exposure to proinflammatory cytokines reveals a marked plasticity of the beta-cell regulatory landscape. We expand the repertoire of human islet regulatory elements by mapping stimulus-responsive enhancers linked to changes in the beta-cell transcriptome, proteome and three-dimensional chromatin structure. Our data indicate that the beta-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 beta cells. Our study illustrates how beta cells respond to a proinflammatory environment and implicate a role for stimulus response islet enhancers in T1D.
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