Differential co-expression network analysis with DCoNA reveals isomiR targeting aberrations in prostate cancer.

MOTIVATION: One of the standard methods of high-throughput RNA sequencing analysis is differential expression. However, it does not detect changes in molecular regulation. In contrast to the standard differential expression analysis, differential co-expression one aims to detect pairs or clusters whose mutual expression changes between two conditions. RESULTS: We developed Differential Co-expression Network Analysis (DCoNA)-an open-source statistical tool that allows one to identify pair interactions, which correlation significantly changes between two conditions. Comparing DCoNA with the state-of-the-art analog, we showed that DCoNA is a faster, more accurate and less memory-consuming tool. We applied DCoNA to prostate mRNA/miRNA-seq data collected from The Cancer Genome Atlas (TCGA) and compared predicted regulatory interactions of miRNA isoforms (isomiRs) and their target mRNAs between normal and cancer samples. As a result, almost all highly expressed isomiRs lost negative correlation with their targets in prostate cancer samples compared to ones without the pathology. One exception to this trend was the canonical isomiR of hsa-miR-93-5p acquiring cancer-specific targets. Further analysis showed that cancer aggressiveness simultaneously increased with the expression level of this isomiR in both TCGA primary tumor samples and 153 blood plasma samples of P. Hertsen Moscow Oncology Research Institute patients' cohort analyzed by miRNA microarrays. AVAILABILITY AND IMPLEMENTATION: Source code and documentation of DCoNA are available at https://github.com/zhiyanov/DCoNA. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A novel approach for a joint analysis of isomiR and mRNA expression data reveals features of isomiR targeting in breast cancer.

A widely used procedure for selecting significant miRNA-mRNA or isomiR-mRNA pairs out of predicted interactions involves calculating the correlation between expression levels of miRNAs/isomiRs and mRNAs in a series of samples. In this manuscript, we aimed to assess the validity of this procedure by comparing isomiR-mRNA correlation profiles in sets of sequence-based predicted target mRNAs and non-target mRNAs (negative controls). Target prediction was carried out using RNA22 and TargetScan algorithms. Spearman's correlation analysis was conducted using miRNA and mRNA sequencing data of The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) project. Luminal A, luminal B, basal-like breast cancer subtypes, and adjacent normal tissue samples were analyzed separately. Using the sets of putative targets and non-targets, we introduced adjusted isomiR targeting activity (ITA)-the number of negatively correlated potential isomiR targets adjusted by the background (estimated using non-target mRNAs). We found that for most isomiRs a significant negative correlation between isomiR-mRNA expression levels appeared more often in a set of predicted targets compared to the non-targets. This trend was detected for both classical seed region binding types (8mer, 7mer-m8, 7mer-A1, 6mer) predicted by TargetScan and the non-classical ones (G:U wobbles and up to one mismatch or unpaired nucleotide within seed sequence) predicted by RNA22. Adjusted ITA distributions were similar for target sites located in 3'-UTRs and coding mRNA sequences, while 5'-UTRs had much lower scores. Finally, we observed strong cancer subtype-specific patterns of isomiR activity, highlighting the differences between breast cancer molecular subtypes and normal tissues. Surprisingly, our target prediction- and correlation-based estimates of isomiR activities were practically non-correlated with the average isomiR expression levels neither in cancerous nor in normal samples.

ECM-Receptor Regulatory Network and Its Prognostic Role in Colorectal Cancer.

Interactions of the extracellular matrix (ECM) and cellular receptors constitute one of the crucial pathways involved in colorectal cancer progression and metastasis. With the use of bioinformatics analysis, we comprehensively evaluated the prognostic information concentrated in the genes from this pathway. First, we constructed a ECM-receptor regulatory network by integrating the transcription factor (TF) and 5'-isomiR interaction databases with mRNA/miRNA-seq data from The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD). Notably, one-third of interactions mediated by 5'-isomiRs was represented by noncanonical isomiRs (isomiRs, whose 5'-end sequence did not match with the canonical miRBase version). Then, exhaustive search-based feature selection was used to fit prognostic signatures composed of nodes from the network for overall survival prediction. Two reliable prognostic signatures were identified and validated on the independent The Cancer Genome Atlas Rectum Adenocarcinoma (TCGA-READ) cohort. The first signature was made up by six genes, directly involved in ECM-receptor interaction: AGRN, DAG1, FN1, ITGA5, THBS3, and TNC (concordance index 0.61, logrank test p = 0.0164, 3-years ROC AUC = 0.68). The second hybrid signature was composed of three regulators: hsa-miR-32-5p, NR1H2, and SNAI1 (concordance index 0.64, logrank test p = 0.0229, 3-years ROC AUC = 0.71). While hsa-miR-32-5p exclusively regulated ECM-related genes (COL1A2 and ITGA5), NR1H2 and SNAI1 also targeted other pathways (adhesion, cell cycle, and cell division). Concordant distributions of the respective risk scores across four stages of colorectal cancer and adjacent normal mucosa additionally confirmed reliability of the models.

Potential role of cellular miRNAs in coronavirus-host interplay.

Host miRNAs are known as important regulators of virus replication and pathogenesis. They can interact with various viruses through several possible mechanisms including direct binding of viral RNA. Identification of human miRNAs involved in coronavirus-host interplay becomes important due to the ongoing COVID-19 pandemic. In this article we performed computational prediction of high-confidence direct interactions between miRNAs and seven human coronavirus RNAs. As a result, we identified six miRNAs (miR-21-3p, miR-195-5p, miR-16-5p, miR-3065-5p, miR-424-5p and miR-421) with high binding probability across all analyzed viruses. Further bioinformatic analysis of binding sites revealed high conservativity of miRNA binding regions within RNAs of human coronaviruses and their strains. In order to discover the entire miRNA-virus interplay we further analyzed lungs miRNome of SARS-CoV infected mice using publicly available miRNA sequencing data. We found that miRNA miR-21-3p has the largest probability of binding the human coronavirus RNAs and being dramatically up-regulated in mouse lungs during infection induced by SARS-CoV.