MiRImpact, a new bioinformatic method using complete microRNA expression profiles to assess their overall influence on the activity of intracellular molecular pathways

Abstract

MicroRNAs (miRs) are short noncoding RNA molecules that regulate expression of target mRNAs. Many published sources provide information about miRs and their targets. However, bioinformatic tools elucidating higher level impact of the established total miR profiles, are still largely missing. Recently, we developed a method termed OncoFinder enabling quantification of the activities of intracellular molecular pathways basing on gene expression data. Here we propose a new technique, MiRImpact, which enables to link miR expression data with its estimated outcome on the regulation of molecular pathways, like signaling, metabolic, cytoskeleton rearrangement, and DNA repair pathways. MiRImpact uses OncoFinder rationale for pathway activity calculations, with the major distinctions that (i) it deals with the concentrations of miRs - known regulators of gene products participating in molecular pathways, and (ii) miRs are considered as negative regulators of target molecules, if other is not specified. MiRImpact operates with 2 types of databases: for molecular targets of miRs and for gene products participating in molecular pathways. We applied MiRImpact to compare regulation of human bladder cancer-specific signaling pathways at the levels of mRNA and miR expression. We took 2 most complete alternative databases of experimentally validated miR targets – miRTarBase and DianaTarBase, and an OncoFinder database featuring 2725 gene products and 271 signaling pathways. We showed that the impact of miRs is orthogonal to pathway regulation at the mRNA level, which stresses the importance of studying posttranscriptional regulation of gene expression. We also report characteristic set of miR and mRNA regulation features linked with bladder cancer.

Early stage of cytomegalovirus infection suppresses host microRNA expression regulation in human fibroblasts

“…These profiles were markedly different for the fibroblasts with high and low sensitivity to infection at both levels of RNA regulation. Similarly to the previously published data for bladder cancer, 23 we observed that the intracellular pathway regulation at the miR level differs greatly from that at the mRNA level, thus showing orthogonal dependencies for the extent of pathway activation (Fig. 4).…”

“…To assess pathway regulation at the microRNA (miR) level, we used the MiRImpact method recently developed in our consortium. 23 The algorithm MiRImpact was built to characterize the effects, provoked by the changes in overall miR concentrations. It quantifies their impact on the activity of intracellular molecular pathways.…”

“…To date, OncoFinder algorithm has been applied for various objects, including induced stem cells, 16 asthma, 17 leukemia, 18 and solid tumors, [19][20] Hutchinson-Gilford and age-related macular degeneration diseases. [21][22] On the other hand, to assess the overall effects of miR expression profiles during HCMV infection, we applied another recent method, termed MiRImpact, 23 which utilizes OncoFinder rationale for pathway activity calculations, but with the distinctions that (i) it processes concentrations of miRs that are known regulators of genes participating in molecular pathways, and (ii) miRs are considered as negative regulators of their target molecules. MiRImpact operates with 2 types of databases: for molecular targets of miRs and for gene products participating in molecular pathways.…”

Chemo brain: From discerning mechanisms to lifting the brain fog—An aging connection

“…Recent modifications to the OncoFinder algorithm allow the personalized screening of nootropic drugs, 60 as well as the analysis of the effects of small RNA (MiRImpact) on signaling pathways. 61 With thorough animal studies, OncoFinder and MiRImpact may be further developed and enabled to predict possible targeted chemotherapy-induced brain side effects.…”

Comprehensive analysis of human microRNA-mRNA interactome

“…Notably, the changes in expression of microRNA may also affect expression levels of other, non-target mRNAs, for example, due miRNA targeting of their upstream regulators. Consequently, newer, more comprehensive approaches, like miRImpact (Artcibasova et al, 2016), PanMiRa (Li and Zhang, 2014), and ProMISe (Li et al, 2014), aim at explaining complex phenotypes by performing analysis of each microRNAs along with its direct and indirect targets.…”