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

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.

SUBMITTER: Colli ML

PROVIDER: S-EPMC7244579 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Colli Maikel L ML Ramos-Rodríguez Mireia M Nakayasu Ernesto S ES Alvelos Maria I MI Lopes Miguel M Hill Jessica L E JLE Turatsinze Jean-Valery JV Coomans de Brachène Alexandra A Russell Mark A MA Raurell-Vila Helena H Castela Angela A Juan-Mateu Jonàs J Webb-Robertson Bobbie-Jo M BM Krogvold Lars L Dahl-Jorgensen Knut K Marselli Lorella L Marchetti Piero P Richardson Sarah J SJ Morgan Noel G NG Metz Thomas O TO Pasquali Lorenzo L Eizirik Décio L DL

Nature communications 20200522 1

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 alt ...[more]

PMID: 32444635

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Project description:Organising pneumonia (OP) is one of the most common and lethal diseases in the category of interstitial pneumonia, along with lung cancer. Reprogramming of lipid metabolism is a newly recognized hallmark of many diseases including cancer, cardiovascular disorders, as well as liver fibrosis and sclerosis. Increased levels of ceramides composed of sphingosine and fatty acid, are implicated in the development of both acute and chronic lung diseases. However, their pathophysiological significance in OP is unclear. The aim of this study was to investigate the role of lipid metabolism reprogramming in OP, focusing on inflammation and fibrosis. Comprehensive multi-omics profiling approaches, including single-cell RNA sequencing, Visium CytAssist spatial transcriptomics, proteomics, metabolomics and mass spectrometry, were employed to analyze the tissues. OP mice model was utilized and molecular mechanisms were investigated in macrophages. The results revealed a significant association between OP and lipid metabolism reprogramming, characterized by an abnormal expression of several genes related to lipid metabolism, including CD36, SCD1, and CES1 mainly in macrophages. CD36 deficiency in alveolar macrophages, led to an increased expression of C16/24 ceramides that accumulated in mitochondria, resulting in mitophagy or mitochondrial dysfunction. The number of alveolar macrophages in OP was significantly reduced, which was probably due to the ferroptosis signaling pathway involving GSH/SLC3A2/GPX4 through CD36 downregulation in OP. Furthermore, macrophage secretion of DPP7 and FABP4 influenced epithelial cell fibrosis. CD36 inhibited the ferroptosis pathway involving SLC3A2/GPX4 in alveolar macrophages of OP tissue by regulating lipid metabolism, thus representing a new anti-ferroptosis and anti-fibrosis effect of CD36 mediated, at least in part, by ceramides. Our findings reveal a significant association between organising pneumonia and lipid metabolism reprogramming and will make a substantial contribution to the understanding of the mechanism of organising pneumonia in patients.

Dataset Information

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

Publications

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

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