An integrated multi-omics approach identifies the landscape of interferon-α-mediated responses of human pancreatic beta cells
Nature Communications. 2020-05-22;11(1):2584.
- 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.
- Consortium data used in this publication
- All raw and processed ATAC and RNA-sequencing data that support the findings of this study have been deposited in NCBI Gene Expression Omnibus (GEO) with the primary accession code GSE133221 (subseries are GSE133218: RNA-seq of EndoC-βH1 cells, GSE148058: RNA-seq of human islets, GSE133219: ATAC-seq of EndoC-βH1 cells). The proteomics datasets have been submitted to Pride under identifier number PXD014244 (http://www.ebi.ac.uk/pride/archive/projects/PXD014244).
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