Gene bi-targeting by viral and human miRNAs

MicroRNAs (miRNAs) are an abundant class of small noncoding RNAs (20-24 nts) that can affect gene expression by post-transcriptional regulation of mRNAs. They play important roles in several biological processes (e.g., development and cell cycle regulation). Numerous bioinformatics methods have been developed to identify the function of miRNAs by predicting their target mRNAs. Some viral organisms also encode miRNAs, a fact that contributes to the complex interactions between viruses and their hosts. A need arises to understand the functional relationship between viral and host miRNAs and their effect on viral and host genes. Our approach to meet this challenge is to identify modules where viral and host miRNAs cooperatively regulate host gene expression.

We present a method to identify groups of viral and host miRNAs that cooperate in post-transcriptional gene regulation, and their target genes that are involved in similar biological processes. We call these groups (genes and miRNAs of human and viral origin) - modules. The modules are found in a new two-stage procedure, which we call bi-targeting, and is presented in this paper. The stages are (i) a new and efficient target prediction, and (ii) a new method for clustering objects of three different data types. In this work we integrate multiple information sources, including miRNA-target binding information, miRNA expression profiles, and GO annotations. Our hypotheses and the methods have been tested on human and Epstein Barr virus (EBV) miRNAs and human genes, for which we found 34 modules. We provide supporting evidence from biological and medical literature for two of our modules. Our code and data are available at http://www.cs.bgu.ac.il/~vaksler/BiTargeting.htm

The presented algorithm, which makes use of diverse biological data, is demonstrated to be an efficient approach for finding bi-targeting modules of viral and human miRNAs. These modules can contribute to a better understanding of viral-host interactions and the role that miRNAs play in them.