Reconstruction and Analysis of circRNA-miRNAmRNA Regulatory Network for Exploring Underlying Pathogenesis of Multiple Sclerosis (MS)

Multiple sclerosis (MS) is a multifactorial, inflammatory, and neurodegenerative disorder affecting the myelinated axons of the central nervous system causing neurological deterioration. Despite more than 40 years of MS research its etiology remains unknown. The current study was aimed at identifying key genes and molecular mechanism in MS. Materials and Methods: Gene expression datasets (GSE17846,GSE31568, GSE39643, GSE61741, GSE17048 and GSE21942) were downloaded from Gene Expression Omnibus (GEO) for integrated bioinformatics analysis. Interactions between differentially expressed miRNAs, mRNAs and lncRNAs were predicted and mergedwith the target genes. Co-expression of miRNAs, lncRNAs and mRNAs was selected to construct mRNAmiRNA - lncRNA interaction networks. Additionally, circRNA–miRNA–mRNA regulatory networks were visualized using Cytoscape. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed for the DEGs. Protein-protein interaction (PPI) networkswere constructed, and transcription factors were annotated. Results: According to the cut-off criteria (adjusted P-value < 0.05 and |log2FC| > 1.0), a total of 457 miRNAs, 660 mRNAs and 23 lncRNAs were differentially expressed in MS. The DE mRNAs were mainly enriched in the nuclei and cytoplasm. Enrichment analysis for all the DE mRNAs showed that they mainly enriched in lymphocyte activation, Hematopoietic cell lineage and myeloid leukocyte activation. Subsequently, pathways interrelation analysis of hub genes was carried out using plug-in ClueGO v2.3.3. The miRNAs were linked to immunological and neurological pathways, and we exposed hsa-let-7b-5p, hsa-miR-664a-3pand hsa-miR-142-3p as promising blood-derived disease biomarkers in MS. Furthermore, we found that 3 miRNAs, 6 lncRNAs, 4 mRNAs and 3 TFs play important regulatory roles in the interaction network. Conclusion: This study revealed the potential pathways and circRNA, miRNA, mRNA, lncRNAs regulatory networks in MS which may contribute to a more comprehensive understanding of MS pathogenesis