Lesion-specific circular RNA and mRNA signatures in secondary progressive multiple sclerosis

Circular RNAs (circRNAs) are single-stranded RNAs with a covalently closed loop structure which have been increasingly recognised as stable and functionally relevant regulators of gene expression via sponging miRNAs. Recently, studies have revealed their roles in human diseases, subsequently emerging as potential biomarkers. Multiple sclerosis (MS) is an inflammatory, neurodegenerative, and immune-related disease of the central nervous system characterised by distinct lesion types that reflect different stages of brain tissue injury and repair. Our study conducted a comprehensive transcriptomic analysis of circRNAs and linear mRNAs across secondary progressive MS (SPMS) lesion types, including normal-appearing white matter, active lesions, chronic active lesions, inactive lesions, and control white matter tissue. Using RNA-seq data and bioinformatics-based analysis, we identified lesion-specific circRNAs and linear transcripts signatures and visualised their expression patterns across samples using row-scaled heatmaps. Functional enrichment analysis revealed that dysregulated circRNAs were associated with synaptic organisation, intracellular signalling, immune responses, and chromatin regulation. To explore potential regulatory mechanisms, we constructed hub genes networks for circQSER1-hsa-miR-6891-5p/hsa-miR-6758-5p-SCD, circFMN2-hsa-miR-4728-5p-SCD axes from down-regulated active lesion type, circCCDC7-hsa-miR-4659b-3p-HBEGF axes from chronic active lesion type for circRNA-miRNA-mRNA. Detailed visualisation of the circRNAs that were identified to be involved in the axes demonstrated extensive isoform diversity and circularisation events within key loci. Our results highlight that circRNAs-associated networks exhibit lesion-specific expression and structural diversity in SPMS and may participate in MS-associated biological processes. This study provides a deeper understanding of circRNAs dysregulation across lesion types and uncovers potential candidate targets and candidate regulatory axes.