A ceRNA Hypothesis: The Rosetta Stone of a Hidden ..

MicroRNAs are small noncoding RNAs that regulate genes post-transciptionally by binding and degrading target eukaryotic mRNAs. We use a quantitative model to study gene regulation by inhibitory microRNAs and compare it to gene regulation by prokaryotic small non-coding RNAs (sRNAs). Our model uses a combination of analytic techniques as well as computational simulations to calculate the mean-expression and noise profiles of genes regulated by both microRNAs and sRNAs. We find that despite very different molecular machinery and modes of action (catalytic vs stoichiometric), the mean expression levels and noise profiles of microRNA-regulated genes are almost identical to genes regulated by prokaryotic sRNAs. This behavior is extremely robust and persists across a wide range of biologically relevant parameters. We extend our model to study crosstalk between multiple mRNAs that are regulated by a single microRNA and show that noise is a sensitive measure of microRNA-mediated interaction between mRNAs. We conclude by discussing possible experimental strategies for uncovering the microRNA-mRNA interactions and testing the competing endogenous RNA (ceRNA) hypothesis.

A ceRNA Hypothesis: The Rosetta Stone of a Hidden …

(2011) A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language?

A ceRNA Hypothesis: The Rosetta Stone of a HIdden …

Recent studies have reported that competitive endogenous RNAs (ceRNAs) can act as sponges for a microRNA (miRNA) through their binding sites and that changes in ceRNA abundances from individual genes can modulate the miRNA’s activity. Consideration of this hypothesis would benefit from knowing the quantitative relationship between a miRNA and its endogenous target sites. Here, we altered intracellular target-site abundance through expression of a miR-122 target in hepatocytes and livers, and analyzed the effects on miR-122 target genes. Target repression was released in a threshold-like manner at high target-site abundance (≥1.5×105 added target sites per cell), and this threshold was insensitive to the effective levels of the miRNA. Furthermore, in response to extreme metabolic liver disease models, global target-site abundance of hepatocytes did not change sufficiently to affect miRNA-mediated repression. Thus, modulation of miRNA target abundance is unlikely to cause significant effects on gene expression and metabolism through a ceRNA effect.

A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language

Highly expressed, site-containing RNAs, either found naturally or delivered as research reagents, can act as “sponges” to titrate miRNAs away from other normal targets (; ; ; ; ). Theoretical and experimental reports have claimed that crosstalk between site-containing RNAs extends far beyond a few highly expressed sponges. Analyses of high-throughput datasets indicate that the activity of a miRNA is not just dependent on its levels, but also its relative target-site abundance, defined as the relative number of sites within the transcriptome for that miRNA (; ). One hypothesis suggests that this crosstalk has a widespread regulatory function, with the act of titrating miRNAs away from their other targets somehow explaining why so many target sites have been conserved in evolution (). This idea is extended to the notion that many miRNA targets act as competitive endogenous RNAs (ceRNAs) that modulate the repression of other targets as their expression increases or decreases (; ). Experimental evidence for such a ceRNA crosstalk was initially described for the tumor-suppressor gene PTEN, which appears to be regulated by the abundance of its pseudogene (PTENP1) in a DICER-dependent manner (). Recent studies have reported the potential physiological relevance of other ceRNAs, including a long non-coding RNA (lncRNA) regulating muscle differentiation (), an overexpressed 3′ untranslated region (3′UTR) inducing cancer in transgenic mice (), and a circular RNA regulating miR-7 activity in the central nervous system (; ). However, such studies have used cancer cell lines with abnormal miRNA and ceRNA expression (; ), leaving their physiological relevance in primary cells unclear.

A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language?
The ceRNA hypothesis and the non-coding revolution in cancer research and therapy [abstract]

Assessing the ceRNA hypothesis with quantitative ..

Regulation of gene expression by microRNAs whichguide the RNA-induced silencing complex (RISC) to microRNA responseelements (MREs) on target transcripts is ubiquitous among mammals,usually resulting in degradation of the transcript or translationinhibition (). Aberrantexpression-fluctuation of a large number of miRNAs has been foundin cancer (,). Recently, numerous experimentsprovide support to the hypothesis that RNA molecules that shareMREs can regulate each other by competing for microRNA binding, forwhich the process is termed competing endogenous RNA (ceRNA)regulation (–). An pseudogene,, has been observed to regulate OCT4A expression asan miR-145 sponge in hepatocellular carcinoma (). Unfortunately, miR-145 isdownregulated in most types of cancers, which confines the strengthof this regulation (–). ceRNA regulation mediated by severalpseudogenes has been demonstrated. Yet, whether or not thisregulation exists among transcript isoforms and the relatedmechanism have not been elucidated. Consistent with theco-expression of OCT4A and OCT4B, we hypothesized that OCT4Bregulates OCT4A as ceRNA.

Assessing the ceRNA hypothesis with quantitative measurements of miRNA and target abundance.

1: Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP

Salmena L, Poliseno L, Tay Y, Kats L andPandolfi PP: A ceRNA hypothesis: The Rosetta Stone of a hidden RNAlanguage? Cell. 146:353–358. 2011. : :

Linc2GO | A human LincRNA function annotation resource based on ceRNA hypothesis

Systematic exploration of autonomous modules in …