A Spanish study showed that relapse and remission in multiple sclerosis (MS) states are regulated by small non-coding RNA (sncRNA) molecules in patterns differing between men and women.
Scientists have increasingly realized that sncRNAs play an important role in the regulation of gene expression. Various kinds of these RNA molecules, such as micro RNA (miRNA) or small nucleolar RNA (snoRNA), can bind to DNA and increase or decrease gene expression.
The research team from the Biodonostia Institute, San Sebastian, Spain, wanted to explore if this type of gene regulation affects the cycles in relapsing-remitting MS (RRMS). They collected blood samples from 24 individuals with RRMS and an equal number of controls. Two blood samples were drawn from the MS patients, during remission and again during relapse.
According to the article — “SncRNA (microRNA & snoRNA) opposite expression pattern found in multiple sclerosis relapse and remission is sex dependent“ — the researchers isolated RNA from immune cells in the blood samples, and analyzed the relative amounts of sncRNAs. Since rates and clinical features differ between men and women, the team analyzed the results based on sex, but also analyzed the group as a whole.
To exclude any possibility that altered treatment induced changes in RNA levels, only patients who were receiving the same treatment in both disease phases were included in the comparison between relapse and remission. This resulted in two groups of patients — 13 receiving the same treatment during relapse and remission, and another 11 who received different treatment. When the team compared patients with healthy controls, all 24 MS patients were included in the analyses.
Investigating the expression of sncRNAs using a microarray, the team identified 23 sncRNAs that were dysregulated in relapse. The results, published in the journal Scientific Reports, also showed that when dividing the analysis by sex, 38 sncRNAs were differentially expressed in women and none in men. Likewise, the team observed 51 altered sncRNAs in remission when looking at all samples, as well as 42 in samples from women, and seven in samples from men.
The scientists hypothesized that if some of these sncRNAs were dysregulated in both relapse and remission states, these might be important for the biology of the disease. The team identified 10 sncRNAs that were common between relapse and remission states, and different from controls. When only including women, eight sncRNAs remained altered. Among these, almost all were dysregulated in opposite directions during remission and relapse.
The team then continued analyzing possible biological pathways affected by these sncRNAs. Using databases and prediction algorithms, researchers created maps of how these factors interact with genes. They observed that in women during relapse, a number of biological processes seemed to be involved. Among these processes, the team noticed regulation of glucose and carbohydrate transport, biosynthetic processes of cell membrane lipids, control of cell division and of the interferon-gamma (IFN-γ) inflammatory signaling pathway, and a regulation of phosphate metabolic processes. In remission, the analysis indicated genes involved in the regulation and execution of innate immune responses, as well as homeostasis of several cell types.
In contrast to the complex networks of genes and sncRNAs observed in women, the networks in men during remission were of low complexity involving relatively few genes, with no particular biological processes over-represented among the genes.
The study clearly showed that expression of sncRNAs vary between the different disease states of RRMS. Also, these differences are not the same for men and women, particularly in relapse, where men did not show any alterations of sncRNA expression. Sex hormones have been implicated in differences in sncRNA expression, and the results clearly show that sex need to be taken into account when treating MS patients. The opposite expression patterns seen in the two MS phases may also give researchers clues about the mechanisms involved in triggering relapse and remission states.