Integrated transcriptional and competitive endogenous RNA networks are cross-regulated in permissive molecular environments

Abstract

Competitive endogenous (ce)RNAs cross-regulate each other through sequestration of shared microRNAs and form complex regulatory networks based on their microRNA signature. However, the molecular requirements for ceRNA cross-regulation and the extent of ceRNA networks remain unknown. Here, we present a mathematical mass-action model to determine the optimal conditions for ceRNA activity in silico. This model was validated using phosphatase and tensin homolog (PTEN) and its ceRNA VAMP (vesicle-associated membrane protein)-associated protein A (VAPA) as paradigmatic examples. A computational assessment of the complexity of ceRNA networks revealed that transcription factor and ceRNA networks are intimately intertwined. Notably, we found that ceRNA networks are responsive to transcription factor up-regulation or their aberrant expression in cancer. Thus, given optimal molecular conditions, alterations of one ceRNA can have striking effects on integrated ceRNA and transcriptional networks.

Deciphering the rules of ceRNA networks

“…The authors validated this network by ectopically overexpressing the PAX/FKHR fusion transcript in an ERMS cell line, and noting an increase in the expression of some ALK and MET ceRNAs. By interrogating the ceRNET for FOXO1 transcriptional targets, Ala et al (4) find that over 40% of genes upregulated in ARMS compared with ERMS were ceRNAs of FOXO1 targets. The crossregulation of transcription factors and the ceRNET was further demonstrated by modulating miRNA expression and observing the effects on transcription factor ceRNAs.…”

“…By integrating mathematical modeling, informatics, and experimental validation, the Ala et al study (4) provides a significant advance in describing these complex networks in the cell and predicting outcomes of perturbations to the networks. The observation that transcription factors are intimately interconnected with ceRNA networks, and that indirect ceRNA interactions amplify their influence on gene expression, appoints ceRNAs as key players in gene regulation.…”

Model-guided quantitative analysis of microRNA-mediated regulation on competing endogenous RNAs using a synthetic gene circuit

“…The strength of ceRNA regulation is largely determined by the relative abundance and binding strength of ceRNAs and miRNAs and whether the miRNA-bound ceRNA decays through a stoichiometric mechanism or a catalytic mechanism (8)(9)(10). The threshold-like behavior of the ceRNA regulation has been experimentally observed by measuring the abundance of two ceRNAs, phosphatase and tensin homolog (PTEN) and vesicle-associated membrane protein (VAMP)-associated protein A (VAPA) across various cell lines (8). Nevertheless, many quantitative predictions deduced from miRNA-ceRNA computational models have not been experimentally validated.…”

Extensive microRNA-mediated crosstalk between lncRNAs and mRNAs in mouse embryonic stem cells

“…The relatively low transcript abundance of most lncRNAs (Cabili et al 2011;Derrien et al 2012) might be thought to limit their ability to effectively modulate, in a miRNA-dependent manner, mRNA abundance (Ebert and Sharp 2010;Ala et al 2013;Figliuzzi et al 2013;Denzler et al 2014). Nevertheless, some established ceRNAs neither share an unusually high number of predicted MREs with their mRNA targets nor are especially abundant (Cesana et al 2011;Wang et al 2013), which suggests that other factors, such as miRNA-target affinity or miRNA turnover, might explain their efficient crosstalk.…”