The T1D-associated lncRNA Lnc13 modulates human pancreatic β cell inflammation by allele-specific stabilization of STAT1 mRNA
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...
| Autores: | , , , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2020 |
| País: | España |
| Institución: | Universidad del País Vasco |
| Repositorio: | Addi. Archivo Digital para la Docencia y la Investigación |
| OAI Identifier: | oai:addi.ehu.eus:10810/65610 |
| Acceso en línea: | http://hdl.handle.net/10810/65610 |
| Access Level: | acceso abierto |
| Palabra clave: | type 1 diabetes polymorphism lncRNA pancreatic β-cell inflammation |
| Sumario: | 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. |
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