The T1D-associated lncRNA
| Autor: | Itziar, Gonzalez-Moro, Ane, Olazagoitia-Garmendia, Maikel L, Colli, Nadia, Cobo-Vuilleumier, Thomas S, Postler, Lorella, Marselli, Piero, Marchetti, Sankar, Ghosh, Benoit R, Gauthier, Decio L, Eizirik, Ainara, Castellanos-Rubio, Izortze, Santin |
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| Rok vydání: | 2020 |
| Předmět: |
endocrine system
Cell Survival Endocrinology Diabetes and Metabolism RNA Stability Primary Cell Culture MEDLINE Inflammation Bioinformatics Polymorphism Single Nucleotide Jurkat Cells Endocrinology Diabetes mellitus Insulin-Secreting Cells Medicine Humans Genetic Predisposition to Disease RNA Messenger Allele 3' Untranslated Regions Alleles business.industry RNA RNA-Binding Proteins Biological Sciences medicine.disease Long non-coding RNA Up-Regulation Diabetes Mellitus Type 1 HEK293 Cells Poly I-C STAT1 Transcription Factor RNA Viral RNA Long Noncoding medicine.symptom business Signal Transduction |
| Zdroj: | Proc Natl Acad Sci U S A |
| ISSN: | 1091-6490 |
| Popis: | 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, 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). Up-regulation of Lnc13 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, Lnc13 gene disruption in β-cells partially counteracts polyinosinic-polycytidylic acid (PIC)-induced STAT1 and proinflammatory chemokine expression. Furthermore, we observed that PIC, a viral mimetic, induces Lnc13translocation from the nucleus to the cytoplasm promoting the interaction of STAT1 mRNA with (poly[rC] binding protein 2) (PCBP2). Interestingly, Lnc13-PCBP2 interaction regulates the stability of the STAT1 mRNA, sustaining inflammation in β-cells in an allele-specific manner. Our results show that the T1D-associated Lnc13 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. |
| Databáze: | OpenAIRE |
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