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Title: An integrated multi-omics approach identifies the landscape of interferon-α-mediated responses of human pancreatic beta cells

Abstract

Proinflammatory cytokines are important mediators of pancreatic beta cell dysfunction and demise in the early stages of type 1 diabetes (T1D). Interferon-a (IFNa), a type I interferon member, is expressed in the islets of T1D individuals and it is expression and signaling is regulated by both genetic (T1D risk variants) and environmental factors (viral infections) associated to T1D. We presently characterized human beta cells responses to IFNa by combining ATAC-seq, RNA-seq and proteomics assays. The initial beta cell response to IFNa was characterized by major chromatin remodeling, followed by marked changes in transcriptional and translational regulation. IFNa-induced changes in alternative splicing (AS) and first exon usage increased the diversity of transcripts expressed by beta cells. This, combined with changes observed on protein modification/degradation, ER stress and MHC class I, may significantly expand the peptide repertoire presented by beta cells to the immune system. On the other hand, beta cells up-regulated checkpoint proteins, such as PDL1 and HLA-E, that may protect them against the autoimmune assault. Data mining of the present multi-omics analysis led to the identification of two compound classes that revert IFNa effects on human beta cells and may be translated to clinical trials.

Authors:
ORCiD logo [1];  [2]; ORCiD logo [3];  [1];  [1];  [4]; ORCiD logo [1];  [1];  [4];  [2];  [1];  [1];  [3];  [5];  [5]; ORCiD logo [6];  [6]; ORCiD logo [4]; ORCiD logo [4]; ORCiD logo [3] more »; ORCiD logo [7]; ORCiD logo [8] « less
  1. Univ. Libre, Brussels (Belgium). ULB Center for Diabetes Research
  2. Univ. Pompeu Fabra, Barcelona (Spain). Endocrine Regulatory Genomics, Dept. of Experimental & Health Sciences; Germans Trias i Pujol Univ. Hospital and Research Inst., Barcelona (Spain). Endocrine Regulatory Genomics Lab.
  3. Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
  4. Univ. of Exeter Medical School (United Kingdom). Inst. of Biomedical & Clinical Science
  5. Olso Univ. Hospital (Norway). Div. of Pediatric and Adolescent Medicine, Faculty of Medicine
  6. Univ. of Pisa (Italy). Islet Cell Lab.
  7. Univ. Pompeu Fabra, Barcelona (Spain). Endocrine Regulatory Genomics, Dept. of Experimental & Health Sciences; Germans Trias i Pujol Univ. Hospital and Research Inst., Barcelona (Spain). Endocrine Regulatory Genomics Lab.; Josep Carreras Leukaemia Research Inst. (IJC), Barcelona (Spain)
  8. Univ. Libre, Brussels (Belgium). ULB Center for Diabetes Research; Univ. Libre, Brussels (Belgium). WELBIO; Indiana Biosciences Research Inst., Indianapolis, IN (United States)
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE; Fonds National de la Recherche Scientifique (FNRS); T2Dsystems; National Institutes of Health (NIH); JDRF; Spanish Ministry of Economy and Competitiveness; South-Eastern Norway Regional Health Authority; Novo Nordisk Foundation
OSTI Identifier:
1638500
Report Number(s):
PNNL-SA-144581
Journal ID: ISSN 2041-1723
Grant/Contract Number:  
AC05-76RL01830; CR-2015A-06; CR-2019C-04; GA667191; 1UC4DK104166-01; 115797; 261441 PEVNET; 5-CDA-2014-221-A-N; JDRF 25-2012-516; SAF2017-86242-R; RYC-2013-12864
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 11; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; Cell death; cell signalling; systems biology; type 1 diabetes; pancreatic beta cells; pancreatic islets; type 1 interferon; inflammation; apoptosis; alternative splicing; proteomics

Citation Formats

Colli, Maikel L., Ramos-Rodríguez, Mireia, Nakayasu, Ernesto S., Alvelos, Maria I., Lopes, Miguel, Hill, Jessica L. E., Turatsinze, Jean-Valery, Coomans de Brachène, Alexandra, Russell, Mark A., Raurell-Vila, Helena, Castela, Angela, Juan-Mateu, Jonàs, Webb-Robertson, Bobbie-Jo M., Krogvold, Lars, Dahl-Jorgensen, Knut, Marselli, Lorella, Marchetti, Piero, Richardson, Sarah J., Morgan, Noel G., Metz, Thomas O., Pasquali, Lorenzo, and Eizirik, Décio L. An integrated multi-omics approach identifies the landscape of interferon-α-mediated responses of human pancreatic beta cells. United States: N. p., 2020. Web. https://doi.org/10.1038/s41467-020-16327-0.
Colli, Maikel L., Ramos-Rodríguez, Mireia, Nakayasu, Ernesto S., Alvelos, Maria I., Lopes, Miguel, Hill, Jessica L. E., Turatsinze, Jean-Valery, Coomans de Brachène, Alexandra, Russell, Mark A., Raurell-Vila, Helena, Castela, Angela, Juan-Mateu, Jonàs, Webb-Robertson, Bobbie-Jo M., Krogvold, Lars, Dahl-Jorgensen, Knut, Marselli, Lorella, Marchetti, Piero, Richardson, Sarah J., Morgan, Noel G., Metz, Thomas O., Pasquali, Lorenzo, & Eizirik, Décio L. An integrated multi-omics approach identifies the landscape of interferon-α-mediated responses of human pancreatic beta cells. United States. https://doi.org/10.1038/s41467-020-16327-0
Colli, Maikel L., Ramos-Rodríguez, Mireia, Nakayasu, Ernesto S., Alvelos, Maria I., Lopes, Miguel, Hill, Jessica L. E., Turatsinze, Jean-Valery, Coomans de Brachène, Alexandra, Russell, Mark A., Raurell-Vila, Helena, Castela, Angela, Juan-Mateu, Jonàs, Webb-Robertson, Bobbie-Jo M., Krogvold, Lars, Dahl-Jorgensen, Knut, Marselli, Lorella, Marchetti, Piero, Richardson, Sarah J., Morgan, Noel G., Metz, Thomas O., Pasquali, Lorenzo, and Eizirik, Décio L. Fri . "An integrated multi-omics approach identifies the landscape of interferon-α-mediated responses of human pancreatic beta cells". United States. https://doi.org/10.1038/s41467-020-16327-0. https://www.osti.gov/servlets/purl/1638500.
@article{osti_1638500,
title = {An integrated multi-omics approach identifies the landscape of interferon-α-mediated responses of human pancreatic beta cells},
author = {Colli, Maikel L. and Ramos-Rodríguez, Mireia and Nakayasu, Ernesto S. and Alvelos, Maria I. and Lopes, Miguel and Hill, Jessica L. E. and Turatsinze, Jean-Valery and Coomans de Brachène, Alexandra and Russell, Mark A. and Raurell-Vila, Helena and Castela, Angela and Juan-Mateu, Jonàs and Webb-Robertson, Bobbie-Jo M. and Krogvold, Lars and Dahl-Jorgensen, Knut and Marselli, Lorella and Marchetti, Piero and Richardson, Sarah J. and Morgan, Noel G. and Metz, Thomas O. and Pasquali, Lorenzo and Eizirik, Décio L.},
abstractNote = {Proinflammatory cytokines are important mediators of pancreatic beta cell dysfunction and demise in the early stages of type 1 diabetes (T1D). Interferon-a (IFNa), a type I interferon member, is expressed in the islets of T1D individuals and it is expression and signaling is regulated by both genetic (T1D risk variants) and environmental factors (viral infections) associated to T1D. We presently characterized human beta cells responses to IFNa by combining ATAC-seq, RNA-seq and proteomics assays. The initial beta cell response to IFNa was characterized by major chromatin remodeling, followed by marked changes in transcriptional and translational regulation. IFNa-induced changes in alternative splicing (AS) and first exon usage increased the diversity of transcripts expressed by beta cells. This, combined with changes observed on protein modification/degradation, ER stress and MHC class I, may significantly expand the peptide repertoire presented by beta cells to the immune system. On the other hand, beta cells up-regulated checkpoint proteins, such as PDL1 and HLA-E, that may protect them against the autoimmune assault. Data mining of the present multi-omics analysis led to the identification of two compound classes that revert IFNa effects on human beta cells and may be translated to clinical trials.},
doi = {10.1038/s41467-020-16327-0},
journal = {Nature Communications},
number = 1,
volume = 11,
place = {United States},
year = {2020},
month = {5}
}

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