dc.contributor.author | González Moro, Itziar | |
dc.contributor.author | Olazagoitia Garmendia, Ane | |
dc.contributor.author | Colli, Maikel L. | |
dc.contributor.author | Cobo Vuilleumier, Nadia | |
dc.contributor.author | Postler, Thomas S. | |
dc.contributor.author | Marselli, Lorella | |
dc.contributor.author | Marchetti, Piero | |
dc.contributor.author | Ghosh, Sankar | |
dc.contributor.author | Gauthier, Benoit R. | |
dc.contributor.author | Eizirik, Decio L. | |
dc.contributor.author | Castellanos Rubio, Ainara | |
dc.contributor.author | Santín Gómez, Izortze | |
dc.date.accessioned | 2024-02-08T11:27:04Z | |
dc.date.available | 2024-02-08T11:27:04Z | |
dc.date.issued | 2020-03-05 | |
dc.identifier.citation | Proceedings of the National Academy of Sciences (PNAS) 117(16) : 9022-9031 (2020) | es_ES |
dc.identifier.issn | 1091-6490 | |
dc.identifier.uri | http://hdl.handle.net/10810/65610 | |
dc.description.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. | es_ES |
dc.description.sponsorship | Departamento de Sanidad del Gobierno Vasco (2015111068)
Fundación de la Sociedad Española de Diabetes (FSED) t | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | National Academy of Sciences | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.subject | type 1 diabetes | es_ES |
dc.subject | polymorphism | |
dc.subject | lncRNA | |
dc.subject | pancreatic β-cell | |
dc.subject | inflammation | |
dc.title | The T1D-associated lncRNA Lnc13 modulates human pancreatic β cell inflammation by allele-specific stabilization of STAT1 mRNA | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.holder | © 2020, National Academy of Sciences | * |
dc.relation.publisherversion | https://www.pnas.org/doi/10.1073/pnas.1914353117 | |
dc.identifier.doi | 10.1073/pnas.1914353117 | |
dc.departamentoes | Bioquímica y biología molecular | es_ES |
dc.departamentoeu | Biokimika eta biologia molekularra | es_ES |