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.

Significance: The mechanisms by which autoimmunity is triggered/amplified in T1D remain to be clarified, and the lack of this basic understanding hampers efforts to prevent or arrest the disease. Testing the hypothesis that T1D-associated genetic variants in lncRNAs affect important pathways that modify inflammation and pancreatic β-cell survival will increase our understanding of T1D pathogenesis. In the present paper, we describe a molecular mechanism by which the T1D-associated lncRNA Lnc13 regulates 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 for the development of novel 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’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.

Summary: Type 1 diabetes-associated single nucleotide polymorphisms are mainly located in non-coding regions of the human genome. Single nucleotide polymorphisms located in long non-coding RNAs may result in the disruption of their secondary structure, affecting their function. Here, we functionally characterized the virus-induced type 1 diabetes-associated lncRNA ARGI (Antiviral Response Gene Inducer). ARGI upregulation in pancreatic β cells leads to the transcriptional activation of antiviral and pro-inflammatory genes. Upon a viral insult, ARGI is upregulated in the nuclei of pancreatic β cells and binds to CTCF to interact with the regulatory regions of IFNβ and interferon-stimulated genes, promoting their transcriptional activation in an allele-specific manner. The presence of the risk allele for type 1 diabetes in ARGI induces an hyperactivation of type I IFN response in β cells, an expression signature that is present in the pancreas of diabetic patients. These data shed light on the molecular mechanisms by which type 1 diabetes-related single nucleotide polymorphisms in long non-coding RNAs influence pathogenesis at the pancreatic β cell level.

Objectives: Several studies suggest that the first immunogenic insult in celiac disease (CeD) could occur during fetal development. The placenta is a key organ that could link the environment with the genome and future outcomes, including CeD. Our objective is to determine the involvement of placental DNA methylation (DNAm) as potential mediator of the genetic susceptibility to CeD. Methods: We used Summary‐data‐based Mendelian Randomization to infer what part of the susceptibility to CeD acts through DNAm in placenta or peripheral blood. We interrogated whether DNAm of the CpGs identified correlated with the expression of adjacent genes in the same tissues, and repeated the procedure only in cases and controls carrying the HLA‐DQ2 risk haplotype. Results: We identified 248 and 215 CpGs associated with CeD in placenta and blood, respectively. Among the former, the DNAm of seven CpGs correlated with the placental expression of ZFP57 . In contrast, in the latter group, the most represented gene was RNF5 , with DNAm of 11 CpGs correlating with its expression in blood. In HLA‐DQ2 positive individuals, we observed a decrease of placental CpGs associated with CeD, with a remarkable exception in chromosome 2, close to AHSA2 . In blood, we identified 44 CpGs associated with CeD in the HLA region, with HLA‐DPA1 showing the largest number of DNAm‐expression associations. Conclusions: Our results suggest that placenta does not seem to be a crucial effector in CeD, and show potentially causal relationships between blood DNAm and CeD, with independent signals in the HLA, and particularly in the HLA‐DPA1 gene.

Aims This study aims to develop a quantitative method for assessing collagen VI expression in cell cultures, which is crucial for the diagnosis and treatment of collagen VI-related dystrophies. Methods We developed a combined in-cell western (ICW) and on-cell western (OCW) assay, that we have called ‘collablot’ to quantify collagen VI and its organisation in the extracellular matrix of cell cultures from patients and healthy controls. To optimise it, we optimised cell density and the protocols to induce collagen expression in cultures, as well as the cell fixation and permeabilisation methods. This was completed with a thorough selection of collagen antibodies and a collagen hybridising peptide (CHP). We then used collablots to compare cultures from patients and controls and evaluate therapeutic interventions in the cultures. Results Collablots enabled the quantification of collagen VI expression in both control and patient cells, aligning with immunocytochemistry findings and detecting variations in collagen VI expression following treatment of the cultures. Additionally, CHP analysis revealed a marked increase in collagen network disruption in patients compared to the controls. Conclusions The collablot assay represents an optimal method for quantifying collagen VI expression and its organisation in culture and assessing the effect of therapies. Key Points - Evaluating therapies for collagen VI-related dystrophies (COL6-RD) requires the quantification of collagen VI levels. - Collablot assays are a novel method for quantifying collagen VI expression and its structural organisation in cell culture. - Due to the significant role of phenotype heterogeneity in this complex disease, quantifying collagen alone might not be adequate for diagnosing COL6-RD, but the addition of a peptide to quantify collagen disorganisation could help in the characterisation of patient cultures.