An integrated multi-omics approach identifies the landscape of interferon-alpha-mediated responses of human pancreatic beta cells
Por:
Colli, ML, Ramos-Rodriguez, M, Nakayasu, ES, Alvelos, MI, Lopes, M, Hill, JLE, Turatsinze, JV, de Brachene, AC, Russell, MA, Raurell-Vila, H, Castela, A, Juan-Mateu, J, Webb-Robertson, BJM, Krogvold, L, Dahl-Jorgensen, K, Marselli, L, Marchetti, P, Richardson, SJ, Morgan, NG, Metz, TO, Pasquali, L and Eizirik, DL
Publicada:
22 may 2020
Ahead of Print:
22 may 2020
Resumen:
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.
Filiaciones:
Colli, ML:
Univ Libre Bruxelles, Med Fac, ULB Ctr Diabet Res, B-1070 Brussels, Belgium
:
Univ Pompeu Fabra, Dept Expt & Hlth Sci, Endocrine Regulatory Genom, Barcelona 08003, Spain
Germans Trias & Pujol Univ Hosp & Res Inst, Endocrine Regulatory Genom Lab, Badalona, Spain
Nakayasu, ES:
Pacific Northwest Natl Lab, Biol Sci Div, Richland, WA 99352 USA
Alvelos, MI:
Univ Libre Bruxelles, Med Fac, ULB Ctr Diabet Res, B-1070 Brussels, Belgium
Lopes, M:
Univ Libre Bruxelles, Med Fac, ULB Ctr Diabet Res, B-1070 Brussels, Belgium
Hill, JLE:
Univ Exeter, Inst Biomed & Clin Sci, Med Sch, Exeter EX2 5DW, Devon, England
Turatsinze, JV:
Univ Libre Bruxelles, Med Fac, ULB Ctr Diabet Res, B-1070 Brussels, Belgium
de Brachene, AC:
Univ Libre Bruxelles, Med Fac, ULB Ctr Diabet Res, B-1070 Brussels, Belgium
Russell, MA:
Univ Exeter, Inst Biomed & Clin Sci, Med Sch, Exeter EX2 5DW, Devon, England
:
Univ Pompeu Fabra, Dept Expt & Hlth Sci, Endocrine Regulatory Genom, Barcelona 08003, Spain
Germans Trias & Pujol Univ Hosp & Res Inst, Endocrine Regulatory Genom Lab, Badalona, Spain
Castela, A:
Univ Libre Bruxelles, Med Fac, ULB Ctr Diabet Res, B-1070 Brussels, Belgium
Juan-Mateu, J:
Univ Libre Bruxelles, Med Fac, ULB Ctr Diabet Res, B-1070 Brussels, Belgium
Webb-Robertson, BJM:
Pacific Northwest Natl Lab, Biol Sci Div, Richland, WA 99352 USA
Krogvold, L:
Oslo Univ Hosp, Fac Med, Div Pediat & Adolescent Med, Oslo, Norway
Dahl-Jorgensen, K:
Oslo Univ Hosp, Fac Med, Div Pediat & Adolescent Med, Oslo, Norway
Marselli, L:
Univ Pisa, Dept Clin & Expt Med, Islet Cell Lab, I-56126 Pisa, Italy
Marchetti, P:
Univ Pisa, Dept Clin & Expt Med, Islet Cell Lab, I-56126 Pisa, Italy
Richardson, SJ:
Univ Exeter, Inst Biomed & Clin Sci, Med Sch, Exeter EX2 5DW, Devon, England
Morgan, NG:
Univ Exeter, Inst Biomed & Clin Sci, Med Sch, Exeter EX2 5DW, Devon, England
Metz, TO:
Pacific Northwest Natl Lab, Biol Sci Div, Richland, WA 99352 USA
:
Univ Pompeu Fabra, Dept Expt & Hlth Sci, Endocrine Regulatory Genom, Barcelona 08003, Spain
Germans Trias & Pujol Univ Hosp & Res Inst, Endocrine Regulatory Genom Lab, Badalona, Spain
Josep Carreras Leukaemia Res Inst IJC, Barcelona, Catalonia, Spain
Eizirik, DL:
Univ Libre Bruxelles, Med Fac, ULB Ctr Diabet Res, B-1070 Brussels, Belgium
Univ Libre Bruxelles, WELBIO, Brussels, Belgium
Indiana Biosci Res Inst, Indianapolis, IN USA
gold, Green Submitted, Green Published, Green Accepted
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