Abstract
Circular RNAs (circRNAs) are transcripts generated by back-splicing. CircRNAs might regulate cellular processes by different mechanisms, including interaction with miRNAs and RNA-binding proteins. CircRNAs are pleiotropic molecules whose dysregulation has been linked to human diseases and can drive cancer by impacting gene expression and signaling pathways. The detection of circRNAs aberrantly expressed in disease conditions calls for the investigation of their functions. Here, we propose CircIMPACT, a bioinformatics tool for the integrative analysis of circRNA and gene expression data to facilitate the identification and visualization of the genes whose expression varies according to circRNA expression changes. This tool can highlight regulatory axes potentially governed by circRNAs, which can be prioritized for further experimental study. The usefulness of CircIMPACT is exemplified by a case study analysis of bladder cancer RNA-seq data. The link between circHIPK3 and heparanase (HPSE) expression, due to the circHIPK3-miR558-HPSE regulatory axis previously determined by experimental studies on cell lines, was successfully detected. CircIMPACT is freely available at GitHub.
Highlights
Circular RNAs are a class of abundant and stable RNAs that result from the ligation of a downstream splice donor to an upstream splice acceptor [1]
CircIMPACT has been implemented as an R package that integrates circRNA expression with gene expression to allow researchers to identify the most condition-discriminant circRNAs and to predict their impact on gene expression, as a proxy for cell behavior (Figure 1)
For each of the circRNA selected, differential expression and classification analysis are performed over gene expression data to retrieve genes dysregulated according to circRNA expression changes across samples
Summary
Circular RNAs (circRNAs) are a class of abundant and stable RNAs that result from the ligation of a downstream splice donor to an upstream splice acceptor [1]. The progressive discovery of circRNA functions, involvement in biological processes, and oncogenic potential made them attractive molecules for both fundamental and cancer research [2]. CircRNAs regulate cellular processes by acting with different mechanisms (Figure 1), mostly involving sequence-specific binding with other nucleic acids or proteins. One prominent mechanism whereby circRNAs are believed to function is by sponging miRNA, regulating the expression of miRNA-target genes, working as competitive endogenous RNAs (ceRNAs) [3]. Other circRNAs modulate the activity of RNA-binding proteins (RBPs), a large class of molecules involved in a multitude of processes, including the control of cell cycle progression [7] and splicing [8], among others. Since most circRNAs originate from the circularization of coding gene exons, circRNA biogenesis can compete with linear RNA splicing [8]. Beyond exerting functions typical of long non-coding RNAs, circRNAs can be translated into peptides [9,10]
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