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Review
. 2018 Jun;53(3):231-245.
doi: 10.1080/10409238.2018.1447542. Epub 2018 Mar 23.

Complexities of post-transcriptional regulation and the modeling of ceRNA crosstalk

Claire L Smillie  1 , Tamara Sirey  1 , Chris P Ponting  1
Affiliations
Review

Complexities of post-transcriptional regulation and the modeling of ceRNA crosstalk

Claire L Smillie et al. Crit Rev Biochem Mol Biol. 2018 Jun.

Abstract

Control of gene and protein expression is required for cellular homeostasis and is disrupted in disease VSports手机版. Following transcription, mRNA turnover and translation is modulated, most notably by microRNAs (miRNAs). This modulation is controlled by transcriptional and post-transcriptional events that alter the availability of miRNAs for target binding. Recent studies have proposed that some transcripts - termed competitive endogenous RNAs (ceRNAs) - sequester a miRNA and diminish its repressive effects on other transcripts. Such ceRNAs thus mutually alter each other's abundance by competing for binding to a common set of miRNAs. Some question the relevance of ceRNA crosstalk, arguing that an individual transcript, when its abundance lies within a physiological range of gene expression, will fail to compete for miRNA binding due to the high abundance of other miRNA binding sites across the transcriptome. Despite this, some experimental evidence is consistent with the ceRNA hypothesis. In this review, we draw upon existing data to highlight mechanistic and theoretical aspects of ceRNA crosstalk. Our intent is to propose how understanding of ceRNA crosstalk mechanisms can be improved and what evidence is required to demonstrate a ceRNA mechanism. A greater understanding of factors affecting ceRNA crosstalk should shed light on its relevance in physiological states. .

Keywords: RNA-induced silencing complex; competitive endogenous RNA; cooperativity; microRNA; post-transcriptional regulation; subcellular localization. V体育安卓版.

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Figures

None
Graphical abstract
Figure 1.
Figure 1.
Pathway of miRNA biogenesis. The canonical pathway of miRNA biogenesis initiates with transcription of the miRNA sequence to form the pri-miRNA. The pri-miRNA is then cleaved by the microprocessor complex (Drosha-DGCR8) to form a hairpin precursor termed the pre-miRNA. Exportin-5-Ran-GTP exports the pre-miRNA from the nucleus into the cytoplasm where it is further cleaved by Dicer. The functional strand of the mature miRNA is then incorporated into an Argonaute protein as part of the RNA-induced silencing complex. This complex is then able to target mRNAs and repress them via a mechanism of mRNA degradation or translational inhibition.
Figure 2.
Figure 2.
A comparison of models of miRNA targeting and how each relates to the potential for ceRNA crosstalk. In the nonhierarchical model, miRNA molecules bind target transcripts independently of their affinity for their miRNA binding sites. As a result, a ceRNA has to contribute an equivalent number of miRNA binding sites to those already present in the transcriptome before significant derepression of endogenous miRNA target transcripts will be observed. Due to such a high requirement for additional miRNA binding sites, the potential for ceRNA crosstalk is low. In the hierarchical model, miRNA molecules preferentially bind higher affinity sites (8mers) before spreading across low affinity sites. A ceRNA with a high affinity miRNA binding site therefore only has to contribute miRNA binding sites at a number similar to the miRNA molecule count before significant derepression of targets will be observed. Therefore, there is potential for ceRNA crosstalk provided that the miRNA is not highly abundant in comparison to the number of its high affinity binding sites. In the preferential targeting model, certain transcripts are preferentially targeted and repressed by miRNA molecules. In this model, the potential for ceRNA crosstalk is high if the ceRNA is a preferentially targeted transcript. However, it is currently unclear what factors may contribute to preferential targeting (see color version of this figure at www.tandfonline.com/ibmg).
Figure 3.
Figure 3.
Availability and activity of miRNA molecules. Not all miRNA molecules present within a cell are active and available for target gene repression. (A) In cell lines, for example, the majority of AGO:miRNA complexes are actively involved in targeting and repression (La Rocca et al. 2015). (B) In contrast, within tissues, the majority of AGO:miRNA complexes are inactive (La Rocca et al. 2015). The effect of a ceRNA will depend on the number of active AGO:miRNA complexes, with greater crosstalk predicted when a smaller number of AGO:miRNA complexes are active (see color version of this figure at www.tandfonline.com/ibmg).
Figure 4.
Figure 4.
Alternate types of miRNA binding sites. Each site type has a different affinity based upon the extent of base pairing to the miRNA (see color version of this figure at www.tandfonline.com/ibmg).
Figure 5.
Figure 5.
The relative efficacy of miRNA-mediated repression of various site types. It is hypothesized that sites with a greater efficacy of miRNA binding and repression also show a greater efficacy for ceRNA crosstalk. (A) Relative efficacy of canonical site types. (B) Relative efficacy of a single site, versus two sites or two cooperatively spaced sites. (C) Hypothesized efficacy of unstudied site types (e.g. preferential binding sites and additional sub-seed sites) versus a canonical 7mer site (see color version of this figure at www.tandfonline.com/ibmg).
Figure 6.
Figure 6.
Subcellular localization of miRNAs, and other components of the miRNA silencing pathway could alter the extent of miRNA-mediated repression and thus potential for ceRNA crosstalk. (A) Both miRNA target transcripts and AGO:miRNA complexes are localized throughout the cytoplasm. The miRNA, therefore, is able to bind and repress its target transcripts. (B) The miRNA target transcripts are localized throughout the cytoplasm but AGO:miRNA complexes are predominantly localized elsewhere, for example, within mitochondria. Consequently, miRNA-mediated repression of the target transcript would be minimal (see color version of this figure at www.tandfonline.com/ibmg).
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