The circular RNA landscape in multiple sclerosis: Disease-specific associated variants and exon methylation shape circular RNA expression profile

Giulia Cardamone, Elvezia Maria Paraboschi, Giulia Soldà, Giuseppe Liberatore, Valeria Rimoldi, Javier Cibella, Federica Airi, Veronica Tisato, Claudia Cantoni, Francesca Gallia, Donato Gemmati, Laura Piccio, Stefano Duga, Eduardo Nobile-Orazio, Rosanna Asselta

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


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.

Original languageEnglish
Article number104426
JournalMultiple Sclerosis and Related Disorders
StatePublished - Jan 2023


  • Biomarkers
  • Circular RNAs
  • DNA methylation
  • Multiple sclerosis
  • eQTL


Dive into the research topics of 'The circular RNA landscape in multiple sclerosis: Disease-specific associated variants and exon methylation shape circular RNA expression profile'. Together they form a unique fingerprint.

Cite this