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mRNA stability influences gene expression and translation in almost all living organisms, and the levels of mRNA molecules in the cell are determined by a balance between production and decay. Maintaining an accurate balance is crucial for the correct function of a wide variety of biological processes and to maintain an appropriate cellular homeostasis. Long non-coding RNAs (lncRNAs) have been shown to participate in the regulation of gene expression through different molecular mechanisms, including mRNA stabilization. In this review we provide an overview on the molecular mechanisms by which lncRNAs modulate mRNA stability and decay. We focus on how lncRNAs interact with RNA binding proteins and microRNAs to avoid mRNA degradation, and also on how lncRNAs modulate epitranscriptomic marks that directly impact on mRNA stability. LncRNA work in author’s laboratory is supported by European Foundation for the Study of Diabetes (EFSD)-EFSD/JDRF/Lilly Programme on Type 1 Diabetes Research and the Spanish Ministry of Science, Innovation and Universities (PID2019-104475GA-I00) to I.S; and Spanish Ministry of Science, Innovation and Universities (SAF2017-91873-EXP and PGC2018-097573-A-I00) to ACR. M.S.D. and I.G.M. are supported by a Predoctoral Fellowship Grant from the UPV/EHU (Universidad del País Vasco/Euskal Herriko Unibertsitatea) and A.O.G. is supported by a Predoctoral Fellowship Grant from the Education Department of Basque Government.

Type 1 diabetes (T1D) is a complex autoimmune disease in which genetic factors interact with environmental changes (e.g. viral infections) to trigger an autoimmune assault against insulin producing pancreatic β-cells. The majority of T1D-associated single nucleotide polymorphisms (SNPs) lay into non-coding regions of the human genome and many have been predicted to affect the expression, secondary structure and function of long non-coding RNAs (lncRNAs). However, the molecular mechanisms by which these non-coding molecules contribute to T1D pathogenesis remain to be clarified. Lnc10 is a lncRNA harboring a T1D-associated SNP that has been described to control Ebi2 expression in immune cells. Ebi2 is a trans-eQTL that regulates the IRF7-driven inflammatory network (iDIN), an antiviral gene network which is enriched with T1D-associated genes. Taking into account that the T1D-associated SNP is located in Lnc10, our hypothesis is that Lnc10 might be dysregulated in T1D patients, influencing the regulation of the iDIN network at the pancreatic β-cell level and provoking an exacerbated antiviral response, and eventually, β-cell destruction. Preliminary results of our group have demonstrated that diabetogenic stimuli, such as pro-inflammatory cytokines and viral infections, upregulate Lnc10 expression in pancreatic β-cells. Lnc10 is located in the nuclei of β-cells, both in basal and stimulated conditions, suggesting a potential role in transcriptional regulation. Lnc10 overexpression in combination with polyinosinic:polycytidylic acid (PIC) transfection to mimic a viral infection, increased the expression of several antiviral genes of the iDIN pathway, including key genes in type I IFN signaling and antiviral response (STAT1, CXCL1, GBP1, SP110, TAP2, IFITM1, DYNLT1, MAP3K7, CCL2 and ERAP1). Interestingly, the type I IFN signaling has been shown to play a crucial role in the initial stages of T1D pathogenesis in pancreatic β-cells. In conclusion, our results show that Lnc10 is upregulated after a viral infection in pancreatic β-cells. Upregulation of Lnc10 in combination with a viral infection exacerbates the expression of several antiviral genes from the iDIN pathway. Further studies are required to elucidate the molecular mechanisms by which this lncRNA regulates the expression of iDIN genes and to determine its impact in virus-induced β-cell dysfunction and T1D development in genetically susceptible individuals.

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.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract that develops due to the interaction between genetic and environmental factors. More than 160 loci have been associated with IBD, but the functional implication of many of the associated genes remains unclear. N6-Methyladenosine (m6A) is the most abundant internal modification in mRNA. m6A methylation regulates many aspects of mRNA metabolism, playing important roles in the development of several pathologies. Interestingly, SNPs located near or within m6A motifs have been proposed as possible contributors to disease pathogenesis. We hypothesized that certain IBD-associated SNPs could regulate the function of genes involved in IBD development via m6A-dependent mechanisms. We used online available GWAS, m6A and transcriptome data to find differentially expressed genes that harbored m6A-SNPs associated with IBD. Our analysis resulted in five candidate genes corresponding to two of the major IBD subtypes: UBE2L3 and SLC22A4 for Crohn&rsquo, s Disease and TCF19, C6orf47 and SNAPC4 for Ulcerative Colitis. Further analysis using in silico predictions and co-expression analyses in combination with in vitro functional studies showed that our candidate genes seem to be regulated by m6A-dependent mechanisms. These findings provide the first indication of the implication of RNA methylation events in IBD pathogenesis.