Abstract
Differential gene expression analyses to investigate multiple sclerosis (MS) molecular pathogenesis cannot detect genes harboring genetic and/or epigenetic modifications that change the gene functions without affecting their expression. Differential co-expression network approaches may capture changes in functional interactions resulting from these alterations. We re-analyzed 595 mRNA arrays from publicly available datasets by studying changes in gene co-expression networks in MS and in response to interferon (IFN)-β treatment. Interestingly, MS networks show a reduced connectivity relative to the healthy condition, and the treatment activates the transcription of genes and increases their connectivity in MS patients. Importantly, the analysis of changes in gene connectivity in MS patients provides new evidence of association for genes already implicated in MS by single-nucleotide polymorphism studies and that do not show differential expression. This is the case of amiloride-sensitive cation channel 1 neuronal (ACCN1) that shows a reduced number of interacting partners in MS networks, and it is known for its role in synaptic transmission and central nervous system (CNS) development. Furthermore, our study confirms a deregulation of the vitamin D system: among the transcription factors that potentially regulate the deregulated genes, we find TCF3 and SP1 that are both involved in vitamin D3-induced p27Kip1 expression. Unveiling differential network properties allows us to gain systems-level insights into disease mechanisms and may suggest putative targets for the treatment.
Highlights
Multiple sclerosis (MS) is a chronic and progressive autoimmune disease characterized by demyelination and degeneration within the central nervous system (CNS)
Our study aims to complement and integrate current studies that analyze gene expression data in whole blood from MS with a specific clinical form (relapsing-remitting (RR)) patients and healthy controls and in response to IFN-β treatment in MS by using differential gene connectivity methods
This evidence suggests that proper physiological functions depend on coordinated gene transcriptions that are impaired in pathological conditions
Summary
Multiple sclerosis (MS) is a chronic and progressive autoimmune disease characterized by demyelination and degeneration within the CNS. In relation to single nucleotide polymorphisms (SNPs) associated with a given disease, the work of Fairfax et al suggests that certain risk alleles can alter the correlated gene expression profiles of specific genes in a context-specific manner, possibly removing such genes from their normal regulatory influences [11]. In this context, a new trend is emerging in transcriptomic studies in which statistically significant changes in correlations between gene pairs are detected in order to reveal changes in functional interactions and dependencies or coordinated activities of genes in response to specific conditions and perturbations [12]. Their work suggests as potential causal nodes those transcripts having altered co-expression correlations with the greatest number of differentially-expressed transcripts
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