An integrated multi-omics approach identifies the landscape of interferon-\u03b1-mediated responses of human pancreatic beta cells

Máikel Luís Colli ,Knut Dahl‐Jørgensen ,Sarah J Richardson ,Bobbie‐Jo Webb‐Robertson ,Jonàs Juan-Mateu ,Jean-Valéry Turatsinze ,Noel G Morgan ,Alexandra Coomans De Brachène ,Piero Marchetti ,Ernesto Nakayasu ,Helena Raurell‐Vila ,Mireia Ramos-Rodríguez ,Mark A Russell ,Thomas O Metz ,Miguel Lopes ,Lorella Marselli ,Jessica L Hill ,Lorenzo Pasquali ,Maria Inês Alvelos ,Lars Krogvold ,Ângela Castela ,Décio L Eizirik

doi:10.1038/s41467-020-16327-0

Abstract

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.

Highlights

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 Type 1 diabetes (T1D) genetic risk variants and viral infections associated with T1D
In line with previous findings suggesting a role for IFNs on the pathogenesis of T1D13, we found that T1D risk genes expressed in human islets[10,14] are significantly enriched in immune-related pathways, including type I and II interferon regulation/signaling (Supplementary Fig. 2b)
We performed a Rank–Rank Hypergeometric Overlap (RRHO) analysis comparing the log[2] foldchange (FC) ranked list from RNA-seqs of EndoC-βH1 cells and human islets (IFNα-treated vs untreated) against an ranked list of genes obtained from RNA-seq of purified primary beta cells[16] from T1D and healthy individuals (Supplementary Fig. 2c and Supplementary Data 1)

Summary

Introduction

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. Transcriptomic studies revealed that >70% of the T1D risk genes are expressed in human pancreatic beta cells[10], and many of these genes regulate innate immunity and type I IFN signaling[11]. To define the global impact of IFNα on human beta cells, we presently performed an integrative multi-omics analysis (ATAC-seq, RNA-seq and proteomics) of IFNα-treated human beta cells to determine the early, intermediate and late responses to the cytokine. IFNα activates key transcription factors (TFs), including IRF1, which act as a mediator of the crosstalk between beta cells and immune cells via the expression of the checkpoint proteins PDL1 and HLA-E. The integration of highcoverage RNA-seq and ATAC-seq indicates regulatory gene networks and reveals that alternative splicing and different first exon usage are key mechanisms expanding the repertoire of mRNAs and proteins expressed by stressed beta cells. Mining the modules of co-expressed genes and the IFNα beta cell signature against the most recent catalogs of experimental and clinical drugs identifies two potentially interesting therapeutic targets for future trials

Methods

Results

Conclusion