The T1D-associated lncRNA Lnc13 modulates human pancreatic β cell inflammation by allele-specific stabilization of STAT1 mRNA
View/ Open
Date
2020-03-05Author
Olazagoitia Garmendia, Ane
Colli, Maikel L.
Cobo Vuilleumier, Nadia
Postler, Thomas S.
Marselli, Lorella
Marchetti, Piero
Ghosh, Sankar
Gauthier, Benoit R.
Eizirik, Decio L.
Castellanos Rubio, Ainara
Santín Gómez, Izortze
Metadata
Show full item record
Proceedings of the National Academy of Sciences (PNAS) 117(16) : 9022-9031 (2020)
Abstract
The vast majority of type 1 diabetes (T1D) genetic association signals lie in non-coding regions of the human genome. Many have been predicted to affect the expression and secondary structure of long non-coding 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 SNP associated with T1D, namely Lnc13. Human pancreatic islets harboring the T1D-associated SNP risk genotype in Lnc13 (rs917997*CC) showed higher STAT1 expression than islets harboring the heterozygous genotype (rs917997*CT). Upregulation of Lnc13 in pancreatic beta cells increased activation of the pro-inflammatory STAT1 pathway, which correlated with increased production of chemokines in an allele-specific manner. In a mirror image, Lnc13 gene disruption in β cells partially counteracts PIC-induced STAT1 and pro-inflammatory chemokine expression. Furthermore, we observed that PIC, a viral mimetic, induces Lnc13 translocation from the nucleus to the cytoplasm, promoting the interaction of STAT1 mRNA with PCBP2. Interestingly, Lnc13-PCBP2 interaction regulates the stability of the STAT1 mRNA, sustaining inflammation in beta cells in an allele-specific manner.
Our results show that the T1D-associated Lnc13 may contribute to the pathogenesis of T1D by increasing pancreatic beta cell inflammation. These findings provide novel information on the molecular mechanisms by which disease-associated SNPs in lncRNAs influence disease pathogenesis and open the door to the development of novel diagnostic and therapeutic approaches based on lncRNA targeting.