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

• Published in: Nature communications Vol. 11; no. 1; pp. 2584 - 17
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.05.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/51; 13/89; 38/91; 60 APPLIED LIFE SCIENCES; 631/553; 631/80/82; 631/80/86; 692/163/2743/137/1418; 82/47; 82/58; 96; 96/2; 96/21; Alternative splicing; Alternative Splicing - drug effects; Antigens; apoptosis; Beta cells; Cell death; cell signalling; Cells, Cultured; Chromatin - drug effects; Chromatin - metabolism; Chromatin remodeling; Cytokines; Data Mining; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - genetics; Gene expression; Gene Expression Regulation - drug effects; Gene regulation; Gene Regulatory Networks; Health risks; Histocompatibility antigen HLA; Humanities and Social Sciences; Humans; Immune system; inflammation; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - physiology; Interferon; Interferon-alpha - metabolism; Interferon-alpha - pharmacology; Major histocompatibility complex; multidisciplinary; Pancreas; pancreatic beta cells; pancreatic islets; Protein Interaction Maps; Proteins; Proteomics; Science; Science (multidisciplinary); Splicing; systems biology; Transcription; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription Initiation Site; type 1 diabetes; type 1 interferon; α-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-16327-0

Interferon-α (IFNα), 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 IFNα by combining ATAC-seq, RNA-seq and proteomics assays. The initial response to IFNα is characterized by chromatin remodeling, followed by changes in transcriptional and translational regulation. IFNα 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 IFNα effects on human beta cells. The cytokine IFNα 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 IFNα-induced changes in human beta cells at the level of chromatin, mRNA and protein expression.