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

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

B-cell leukemia transdifferentiation to macrophage involves reconfiguration of DNA methylation for long-range regulation

Hematopoiesis is a highly regulated process that, starting from hematopoietic stem cells (HSCs) with self-renewal capacity in the adult human bone marrow, is able to generate all different types of mature blood cells. The classical view of hematopoiesis defines binary branching points from these HSCs that segregate lineages and direct differentiation to terminally differentiated functional cell types [1]. However, the described hierarchical model can be complemented with the emerging data that suggest the existence of hematopoietic stem and progenitor cells with a continuum of transitory differentiation stages, including cells with early lineage priming that generate distinct blood cell types according to the physiological or pathological environment [2]

B-cell leukemia transdifferentiation to macrophage involves reconfiguration of DNA methylation for long-range regulation

Hematopoiesis is a highly regulated process that, starting from hematopoietic stem cells (HSCs) with self-renewal capacity in the adult human bone marrow, is able to generate all different types of mature blood cells. The classical view of hematopoiesis defines binary branching points from these HSCs that segregate lineages and direct differentiation to terminally differentiated functional cell types [1]. However, the described hierarchical model can be complemented with the emerging data that suggest the existence of hematopoietic stem and progenitor cells with a continuum of transitory differentiation stages, including cells with early lineage priming that generate distinct blood cell types according to the physiological or pathological environment [2]

The impact of proinflammatory cytokines on the β-cell regulatory landscape provides insights into the genetics of type 1 diabetes

Early stages of type 1 diabetes (T1D) are characterized by local autoimmune inflammation and progressive loss of insulin-producing pancreatic β cells. We show here that exposure to pro-inflammatory cytokines unmasks a marked plasticity of the β-cell regulatory landscape. We expand the repertoire of human islet regulatory elements by mapping stimulus-responsive enhancers linked to changes in the β-cell transcriptome, proteome and 3D chromatin structure. Our data indicates that the β cell response to cytokines is mediated by the induction of novel regulatory regions as well as the activation of primed regulatory elements pre-bound by islet-specific transcription factors. We found that T1D associated loci are enriched of the newly mapped cis-regulatory regions and identify T1D-associated variants disrupting cytokine-responsive enhancer activity in human β cells. Our study illustrates how β cells respond to a pro-inflammatory environment and implicate a role for stimulus-response islet enhancers in T1D

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

Altres ajuts: This work was supported by grants from Marató TV3 (201624.10 to L.P.). M.R. is supported by an FI Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR) PhD fellowship.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