期刊
NATURE COMMUNICATIONS
卷 11, 期 1, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-020-16327-0
关键词
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资金
- Fonds National de la Recherche Scientifique (FNRS), Welbio, Belgium [CR-2015A-06, CR-2019C-04]
- Horizon 2020 Program, T2Dsystems [GA667191]
- National Institutes of Health
- NIH-NIDDK-HIRN Consortium [1UC4DK104166-01]
- Innovate2CureType1 - Dutch Diabetes Research Fundation (DDRF)
- Innovative Medicines Initiative 2 Joint Undertaking [115797]
- Union's Horizon 2020 research and innovation programme
- EFPIA
- JDRF
- Leona M. and Harry B. Helmsley Charitable Trust
- South-Eastern Norway Regional Health Authority
- Novo Nordisk Foundation
- PEVNET (Persistent Virus Infection in Diabetes Network) Study Group - European Union's Seventh Framework Programme (FP7/2007-2013) [261441 PEVNET]
- JDRF Career Development Award [5-CDA-2014-221-A-N]
- JDRF research grant [JDRF 25-2012-516]
- MRC Project [MR/P010695/1]
- Norman Family Trust
- Spanish Ministry of Economy and Competiveness [SAF2017-86242-R]
- Marato TV3 [201624.10]
- Ramon y Cajal from the Spanish Ministry of Economy and Competitiveness [RYC-2013-12864]
- FI Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR) PhD fellowship
- DOE [DE-AC05-76RLO01830]
- MRC [MR/P010695/1] Funding Source: UKRI
Interferon-alpha (IFN alpha), a type I interferon, is expressed in the islets of type 1 diabetic individuals, and its expression and signaling are regulated by T1D genetic risk variants and viral infections associated with T1D. We presently characterize human beta cell responses to IFN alpha by combining ATAC-seq, RNA-seq and proteomics assays. The initial response to IFN alpha is characterized by chromatin remodeling, followed by changes in transcriptional and translational regulation. IFN alpha induces changes in alternative splicing (AS) and first exon usage, increasing the diversity of transcripts expressed by the beta cells. This, combined with changes observed on protein modification/degradation, ER stress and MHC class I, may expand antigens presented by beta cells to the immune system. Beta cells also up-regulate the checkpoint proteins PDL1 and HLA-E that may exert a protective role against the autoimmune assault. Data mining of the present multi-omics analysis identifies two compound classes that antagonize IFN alpha effects on human beta cells. The cytokine IFN alpha is expressed in the islets of individuals with type 1 diabetes and contributes to local inflammation and destruction of beta cells. Here, the authors provide a global multiomics view of IFN alpha -induced changes in human beta cells at the level of chromatin, mRNA and protein expression.
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