Investigating the Role of MicroRNA and Transcription Factor Co-regulatory Networks in Multiple Sclerosis Pathogenesis

MicroRNAs (miRNAs) and transcription factors (TFs) play key roles in complex multifactorial diseases like multiple sclerosis (MS). Starting from the miRNomic profile previously associated with a co- hort of pediatric MS (PedMS) patients, we applied a combined mo- lecular and computational approach in order to verify published data in patients with adult-onset MS (AOMS). Six out of the 13 selected miRNAs (miR-320a, miR-125a-5p, miR-652-3p, miR-185-5p, miR- 942-5p, miR-25-3p) were significantly upregulated in PedMS and AOMS patients, suggesting that they may be considered circulating biomarkers distinctive of the disease independently from age. A com- putational and unbiased miRNA-based screening of target genes not necessarily associated to MS was then performed in order to provide an extensive view of the genetic mechanisms underlying the disease. A comprehensive MS-specific miRNA-TF co-regulatory network was hypothesized; among others, SP1, RELA, NF-?B, TP53, AR, MYC, HDAC1, and STAT3 regulated the transcription of 61 targets. Inter- estingly, NF-?B and STAT3 cooperatively regulate the expression of immune response genes and control the cross-talk between inflam- matory and immune cells. Further functional analysis will be per- formed on the identified critical hubs. Above all, in our view, this ap- proach supports the need of multidisciplinary strategies for shedding light into the pathogenesis of MS.