miRsponge: an R/Bioconductor package for the identification and analysis of miRNA sponge interaction networks and modules

Abstract

BackgroundA microRNA (miRNA) sponge is an RNA molecule with multiple tandem miRNA response elements that can sequester miRNAs from their target mRNAs. Despite growing appreciation of the importance of miRNA sponges, our knowledge of their complex functions remains limited. Moreover, there is still a lack of miRNA sponge research tools that help researchers to quickly compare their proposed methods with other methods, apply existing methods to new datasets, or select appropriate methods for assisting in subsequent experimental design. ResultsTo fill the gap, we present an R/Bioconductor package, miRspongeR, for simplifying the procedure of identifying and analyzing miRNA sponge interaction networks and modules. It provides seven popular methods and an integrative method to identify miRNA sponge interactions. Moreover, it supports the validation of miRNA sponge interactions and the identification of miRNA sponge modules, as well as functional enrichment and survival analysis of miRNA sponge modules. ConclusionsThis package enables researchers to quickly evaluate their new methods, apply existing methods to new datasets, and consequently speed up miRNA sponge research. Keywords miRNA -ceRNA -miRNA sponge -miRNA sponge interaction networks -miRNA sponge modules -human breast invasive carcinoma Background MicroRNAs (miRNAs) are small non-coding RNAs with ~22 nucleotides. They usually induce repression or translational inhabitation of target genes through partial -3 -complementarities with multiple miRNA response elements (MREs) of the target RNA transcripts [1]. Previous studies [2, 3] have shown that miRNAs are involved in a broad range of biological processes, such as cell cycle control, cell apoptosis, cell differentiation and a diverse range of human cancers. The competing endogenous RNA (ceRNA) hypothesis [4] considers that all types of coding and non-coding RNA transcripts may crosstalk with each other by sharing common miRNAs. By competing with each other, those ceRNAs (also known as miRNA sponges or decoys), including long non-coding RNAs (lncRNAs), pseudogenes, mRNAs and circular RNAs (circRNAs), can release parental target mRNAs from miRNAs' control [5]. The ceRNA hypothesis challenges the traditional knowledge that coding RNAs only act as targets of miRNAs, and it provides a starting point for the investigation of the biological functions and mechanisms of miRNA sponges. Recently, several lncRNAs, pseudogenes, circRNAs and mRNAs acting as miRNA sponges have been experimentally identified and confirmed, together with their important biological functions. For example, linc-MD1, a muscle-specific lncRNA, activates muscle-specific gene expression by regulating the expression of MAML1 and MEF2C via sponging miR-133 and miR-135 [6]. PTENP1, a pseudogene of the PTEN tumor suppression gene, can act as a sponge of PTEN-targeting miRNAs to play a growth-suppressive role [7]. As for circRNAs, CDR1as/ciRS-7 is encoded in the genome antisense to the human CDR1 (gene) locus, and affects the activity of miR-7 target genes...

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“…The ORQ transformation was performed with the bestNormalize R package 15 . Finally, the rsq R package was employed to calculate partial R 2 statistics (i.e., unique variances) 16 . Descriptive statistics of each variable (e.g., means, medians, and quantiles) are retrievable from the R codes provided online.…”