A T1D-associated lncRNA modulates the type I interferon signaling and the antiviral response in pancreatic beta cells

Autor: Izortze Santin, Itziar Gonzalez-Moro
Rok vydání: 2020
Předmět:
Zdroj: BIBM
DOI: 10.1109/bibm49941.2020.9313457
Popis: Type 1 diabetes (T1D) is a complex autoimmune disease in which genetic factors interact with environmental changes (e.g. viral infections) to trigger an autoimmune assault against insulin producing pancreatic β-cells. The majority of T1D-associated single nucleotide polymorphisms (SNPs) lay into non-coding regions of the human genome and many have been predicted to affect the expression, secondary structure and function of long non-coding RNAs (lncRNAs). However, the molecular mechanisms by which these non-coding molecules contribute to T1D pathogenesis remain to be clarified. Lnc10 is a lncRNA harboring a T1D-associated SNP that has been described to control Ebi2 expression in immune cells. Ebi2 is a trans-eQTL that regulates the IRF7-driven inflammatory network (iDIN), an antiviral gene network which is enriched with T1D-associated genes. Taking into account that the T1D-associated SNP is located in Lnc10, our hypothesis is that Lnc10 might be dysregulated in T1D patients, influencing the regulation of the iDIN network at the pancreatic β-cell level and provoking an exacerbated antiviral response, and eventually, β-cell destruction. Preliminary results of our group have demonstrated that diabetogenic stimuli, such as pro-inflammatory cytokines and viral infections, upregulate Lnc10 expression in pancreatic β-cells. Lnc10 is located in the nuclei of β-cells, both in basal and stimulated conditions, suggesting a potential role in transcriptional regulation. Lnc10 overexpression in combination with polyinosinic:polycytidylic acid (PIC) transfection to mimic a viral infection, increased the expression of several antiviral genes of the iDIN pathway, including key genes in type I IFN signaling and antiviral response (STAT1, CXCL1, GBP1, SP110, TAP2, IFITM1, DYNLT1, MAP3K7, CCL2 and ERAP1). Interestingly, the type I IFN signaling has been shown to play a crucial role in the initial stages of T1D pathogenesis in pancreatic β-cells. In conclusion, our results show that Lnc10 is upregulated after a viral infection in pancreatic β-cells. Upregulation of Lnc10 in combination with a viral infection exacerbates the expression of several antiviral genes from the iDIN pathway. Further studies are required to elucidate the molecular mechanisms by which this lncRNA regulates the expression of iDIN genes and to determine its impact in virus-induced β-cell dysfunction and T1D development in genetically susceptible individuals.
Databáze: OpenAIRE
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