The type 1 diabetes-associated lncRNA ARGI participates in virus-induced pancreatic β cell inflammation

Type 1 diabetes-associated single nucleotide polymorphisms are mainly located in non-coding regions of the human genome. Single nucleotide polymorphisms located in long non-coding RNAs may result in the disruption of their secondary structure, affecting their function. Here, we functionally characterized the virus-induced type 1 diabetes-associated lncRNA ARGI (Antiviral Response Gene Inducer). ARGI upregulation in pancreatic β cells leads to the transcriptional activation of antiviral and pro-inflammatory genes. Upon a viral insult, ARGI is upregulated in the nuclei of pancreatic β cells and binds to CTCF to interact with the regulatory regions of IFNβ and interferon-stimulated genes, promoting their transcriptional activation in an allele-specific manner. The presence of the risk allele for type 1 diabetes in ARGI induces an hyperactivation of type I IFN response in β cells, an expression signature that is present in the pancreas of diabetic patients. These data shed light on the molecular mechanisms by which type 1 diabetes-related single nucleotide polymorphisms in long non-coding RNAs influence pathogenesis at the pancreatic β cell level.