The circular RNA landscape in multiple sclerosis: Disease-specific associated variants and exon methylation shape circular RNA expression profile
Document Type
Article
Abstract
BACKGROUND: Circular RNAs (circRNAs) are a class of non-coding RNAs increasingly emerging as crucial actors in the pathogenesis of human diseases, including autoimmune and neurological disorders as multiple sclerosis (MS). Despite several efforts, the mechanisms regulating circRNAs expression are still largely unknown and the circRNA profile and regulation in MS-relevant cell models has not been completely investigated. In this work, we aimed at exploring the global landscape of circRNA expression in MS patients, also evaluating a possible correlation with their genetic and epigenetic background. METHODS: We performed RNA-seq experiments on circRNA-enriched samples, derived from peripheral blood mononuclear cells (PBMCs) of 10 MS patients and 10 matched controls and performed differential circRNA expression. The genetic background was evaluated using array genotyping, and an expression quantitative trait loci (eQTL) analysis was carried out. RESULTS: Expression analysis revealed 166 differentially expressed circRNAs in MS patients, 125 of which are downregulated. One of the top dysregulated circRNAs, hsa_circ_0007990, derives from the PGAP3 gene, encoding a protein relevant for the control of autoimmune responses. The downregulation of this circRNA was confirmed in two independent replication cohorts, suggesting its implementation as a possible RNA-based biomarker. The eQTL analysis evidenced a significant association between 89 MS-associated loci and the expression of at least one circRNA, suggesting that MS-associated variants could impact on disease pathogenesis by altering circRNA profiles. Finally, we found a significant correlation between exon methylation and circRNA expression levels, supporting the hypothesis that epigenetic features may play an important role in the definition of the cell circRNA pool. CONCLUSION: We described the circRNA expression profile of PBMCs in MS patients, suggesting that MS-associated variants may tune the expression levels of circRNAs acting as "circ-QTLs", and proposing a role for exon-based DNA methylation in regulating circRNA expression.
Keywords
Biomarkers, Circular RNAs, DNA methylation, Multiple sclerosis, eQTL
Medical Subject Headings
Humans; RNA, Circular (genetics, metabolism); Leukocytes, Mononuclear (metabolism); Multiple Sclerosis (genetics, metabolism); RNA (genetics, metabolism); DNA Methylation
Publication Date
1-1-2023
Publication Title
Multiple sclerosis and related disorders
E-ISSN
2211-0356
Volume
69
First Page
104426
PubMed ID
36446168
Digital Object Identifier (DOI)
10.1016/j.msard.2022.104426
Recommended Citation
Cardamone, Giulia; Paraboschi, Elvezia Maria; Soldà, Giulia; Liberatore, Giuseppe; Rimoldi, Valeria; Cibella, Javier; Airi, Federica; Tisato, Veronica; Cantoni, Claudia; Gallia, Francesca; Gemmati, Donato; Piccio, Laura; Duga, Stefano; Nobile-Orazio, Eduardo; and Asselta, Rosanna, "The circular RNA landscape in multiple sclerosis: Disease-specific associated variants and exon methylation shape circular RNA expression profile" (2023). Translational Neuroscience. 2350.
https://scholar.barrowneuro.org/neurobiology/2350