TY - JOUR
T1 - The circular RNA landscape in multiple sclerosis
T2 - Disease-specific associated variants and exon methylation shape circular RNA expression profile
AU - Cardamone, Giulia
AU - Paraboschi, Elvezia Maria
AU - Soldà, Giulia
AU - Liberatore, Giuseppe
AU - Rimoldi, Valeria
AU - Cibella, Javier
AU - Airi, Federica
AU - Tisato, Veronica
AU - Cantoni, Claudia
AU - Gallia, Francesca
AU - Gemmati, Donato
AU - Piccio, Laura
AU - Duga, Stefano
AU - Nobile-Orazio, Eduardo
AU - Asselta, Rosanna
N1 - Publisher Copyright:
© 2022
PY - 2023/1
Y1 - 2023/1
N2 - 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.
AB - 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.
KW - Biomarkers
KW - Circular RNAs
KW - DNA methylation
KW - Multiple sclerosis
KW - eQTL
UR - http://www.scopus.com/inward/record.url?scp=85142672833&partnerID=8YFLogxK
U2 - 10.1016/j.msard.2022.104426
DO - 10.1016/j.msard.2022.104426
M3 - Article
C2 - 36446168
AN - SCOPUS:85142672833
SN - 2211-0348
VL - 69
JO - Multiple Sclerosis and Related Disorders
JF - Multiple Sclerosis and Related Disorders
M1 - 104426
ER -