The T1D-associated lncRNA <i>Lnc13</i> modulates human pancreatic β cell inflammation by allele-specific stabilization of <i>STAT1</i> mRNA

Abstract

The vast majority of type 1 diabetes (T1D) genetic association signals lie in noncoding regions of the human genome. Many have been predicted to affect the expression and secondary structure of long noncoding RNAs (lncRNAs), but the contribution of these lncRNAs to the pathogenesis of T1D remains to be clarified. Here, we performed a complete functional characterization of a lncRNA that harbors a single nucleotide polymorphism (SNP) associated with T1D, namely, <i>Lnc13</i> Human pancreatic islets harboring the T1D-associated SNP risk genotype in <i>Lnc13</i> (rs917997*CC) showed higher <i>STAT1</i> expression than islets harboring the heterozygous genotype (rs917997*CT). Up-regulation of <i>Lnc13</i> in pancreatic β-cells increased activation of the proinflammatory STAT1 pathway, which correlated with increased production of chemokines in an allele-specific manner. In a mirror image, <i>Lnc13</i> gene disruption in β-cells partially counteracts polyinosinic-polycytidylic acid (PIC)-induced <i>STAT1</i> and proinflammatory chemokine expression. Furthermore, we observed that PIC, a viral mimetic, induces <i>Lnc13</i> translocation from the nucleus to the cytoplasm promoting the interaction of <i>STAT1</i> mRNA with (poly[rC] binding protein 2) (PCBP2). Interestingly, <i>Lnc13</i>-PCBP2 interaction regulates the stability of the <i>STAT1</i> mRNA, sustaining inflammation in β-cells in an allele-specific manner. Our results show that the T1D-associated <i>Lnc13</i> may contribute to the pathogenesis of T1D by increasing pancreatic β-cell inflammation. These findings provide information on the molecular mechanisms by which disease-associated SNPs in lncRNAs influence disease pathogenesis and open the door to the development of diagnostic and therapeutic approaches based on lncRNA targeting.