Abstract
Multiple sclerosis (MS) is a complex, demyelinating disease with the involvement of autoimmunity and neurodegeneration. Increasing efforts have been made towards identifying the diagnostic markers to differentiate the classes of MS from other similar neurological conditions. Using a systems biology approach, we constructed four types of gene regulatory networks (GRNs) involved in peripheral blood mononuclear cells (PBMCs). The regulatory strength of each GRN across primary progressive MS (PPMS), relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and control were evaluated by an integrity algorithm. Among the constructed GRNs (referred as TF_gene_miRNA), POU3F2_CDK6_hsa-miR-590-3p, MEIS1_CASC3_hsa-miR-1261, STAT3_OGG1_hsa-miR-298, and TCF4_FMR1_hsa-miR-301b were top-ranked and differentially regulated in all classes of MS compared to control. These GRNs showed potential involvement in regulating various molecular pathways such as interleukin, integrin, glypican, sphingosine phosphate, androgen, and Wnt signaling pathways. For validation, the qPCR analysis of the GRN components (TFs, gene, and miRNAs) in PBMCs of healthy controls (n = 30), RRMS (n = 14), PPMS (n = 13) and SPMS (n = 12) were carried out. Real-time expression analysis of GRNs showed a similar regulatory pattern as derived from our systems biology approach. Also, our study provided several novel GRNs that regulate unique and common molecular mechanisms between MS conditions. Hence, these regulatory components of GRNs will help to understand the disease mechanism across MS classes and further insight may though light towards diagnosis.
Highlights
Gene regulatory network (GRN) plays a vital role in normal cellular processes such as metabolism, cell differentiation, cell cycle, and cell signaling
To construct the peripheral blood mononuclear cells (PBMCs) based gene regulatory network, the gene, transcription factor (TF), and miRNA expressed in human PBMCs were collected from microarray platforms
Among 2016172 GRNs, 3092, 53483, 94906 and 1864691 were attributed to clGRNs, gGRNs, tfGRNs, and miRGRNs, respectively. These GRNs were mapped with the microarray expression data of healthy controls, relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS) (4*2016172)
Summary
Gene regulatory network (GRN) plays a vital role in normal cellular processes such as metabolism, cell differentiation, cell cycle, and cell signaling. MiRNA and TF co-regulate each other to form a regulatory network that controls cellular gene expression. Several efforts have been made to understand the GRNs in multiple sclerosis[13,14,15,16] Their studies are compromised while describing the type of GRNs and their regulatory strength contributing to RRMS, PPMS, and SPMS. Our approach identifies a diverse range of the regulatory network that explains the common and unique GRNs between the MS conditions These GRNs regulate several previously known and unknown molecular pathways involved in RRMS, PPMS, and SPMS. QPCR analysis of selected GRN components (TF, gene, and miRNA) confirm the differential regulation in PBMCs of RRMS, PPMS, and SPMS compared to healthy controls. Our study elaborates and highlights the involvement of GRNs in PBMCs of multiple sclerosis which is essential to understand the disease pathogenesis that may throw light towards biomarkers for diagnosis
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