Abstract
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 cohort of pediatric MS (PedMS) patients, we applied a combined molecular 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 computational 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-κB, TP53, AR, MYC, HDAC1, and STAT3 regulated the transcription of 61 targets. Interestingly, NF-κB and STAT3 cooperatively regulate the expression of immune response genes and control the cross-talk between inflammatory and immune cells. Further functional analysis will be performed on the identified critical hubs. Above all, in our view, this approach supports the need of multidisciplinary strategies for shedding light into the pathogenesis of MS.
Highlights
As in other species, the gene regulation process assumes multiple modes, including transcriptional regulation played by the regulatory proteins or transcription factors (TFs), and post-transcriptional regulation by including, most notably, microRNAs
The miRNA repository miRBase (Release 22) [2] currently lists 1917 precursor miRNAs and 2654 mature miRNAs in the human genome; multiple or a cluster of miRNAs cooperatively regulate a given target gene leading to complex regulatory networks [3,4], and multiple genes can be targeted by the same miRNA
In a previous study [19] we investigated the transcriptome profile of peripheral blood samples in a cohort of pediatric MS (PedMS) patients, and we found that 12 mature miRNAs were significantly upregulated and one miRNA was downregulated in PedMS patients compared to pediatric control (PC) subjects
Summary
As in other species, the gene regulation process assumes multiple modes, including transcriptional regulation played by the regulatory proteins or transcription factors (TFs), and post-transcriptional regulation by including, most notably, microRNAs (miRNAs). Given the complex heterogeneity of MS [18], the possibility to identify reliable markers, i.e., predictive of the clinical course or response to treatments, has so far been elusive due to its multifactorial nature that involves several genes and their interactions. To pursue this issue, in a previous study [19] we investigated the transcriptome profile of peripheral blood samples in a cohort of PedMS patients, and we found that 12 mature miRNAs were significantly upregulated (let-7a-5p, let-7b-5p, miR-25-3p, miR-125a-5p, miR-942-5p, miR-221-3p, miR-652-3p, miR-182-5p, miR-185-5p, miR-181a-5p, miR-320a, and miR-99b-5p) and one miRNA was downregulated (miR-148b-3p) in PedMS patients compared to pediatric control (PC) subjects. Based on the obtained results and according to the transcriptional regulatory rule, a comprehensive MS-specific miRNA-TF co-regulatory network was built, suggesting an alternative and valuable approach for the identification of significant regulators and their target genes in MS
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