Abstract
MicroRNAs (miRNAs) are an integral part of gene regulation at the post-transcriptional level. Recently, it has been shown that pairs of miRNAs can repress the translation of a target mRNA in a cooperative manner, which leads to an enhanced effectiveness and specificity in target repression. However, it remains unclear which miRNA pairs can synergize and which genes are target of cooperative miRNA regulation. In this paper, we present a computational workflow for the prediction and analysis of cooperating miRNAs and their mutual target genes, which we refer to as RNA triplexes. The workflow integrates methods of miRNA target prediction; triplex structure analysis; molecular dynamics simulations and mathematical modeling for a reliable prediction of functional RNA triplexes and target repression efficiency. In a case study we analyzed the human genome and identified several thousand targets of cooperative gene regulation. Our results suggest that miRNA cooperativity is a frequent mechanism for an enhanced target repression by pairs of miRNAs facilitating distinctive and fine-tuned target gene expression patterns. Human RNA triplexes predicted and characterized in this study are organized in a web resource at www.sbi.uni-rostock.de/triplexrna/.
Highlights
MicroRNAs are a well conserved and abundant class of ∼22 nt long functional RNA molecules that regulate the expression of most protein coding genes at the posttranscriptional level [1]
Our proposed workflow for the identification and analysis of RNA triplexes in animal genomes includes six steps that sequentially increase the level of detail and confidence in the functionality of the predicted synergistic target regulation (Figure 2)
The main result of our work is the described workflow which can be used to identify RNA triplexes and to determine whether these are functional in terms of cooperative target regulation by two miRNAs
Summary
MicroRNAs (miRNAs) are a well conserved and abundant class of ∼22 nt long functional RNA molecules that regulate the expression of most protein coding genes at the posttranscriptional level [1]. Multiple predictions and growing experimental evidence suggest that many genes are targets of concerted miRNA regulation [1,2,3]. Deregulated miRNAs have been associated with the pathogenesis and the progression of many diseases, including cancer [7]. Another remarkable aspect about miRNAs is that they provide a valuable source for diagnostic and prognostic markers for a growing number of human pathologies; especially those miRNAs found in body fluids [8,9]. For details see the reviews by Seto [10] and Kasinski and Slack [11]
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