MicroRNA - Cellular Functions

Cellular Functions

The function of miRNAs appears to be in gene regulation. For that purpose, a miRNA is complementary to a part of one or more messenger RNAs (mRNAs). Animal miRNAs are usually complementary to a site in the 3' UTR whereas plant miRNAs are usually complementary to coding regions of mRNAs. Perfect or near perfect base pairing with the target RNA promotes cleavage of the RNA. This is the primary mode of plant miRNAs. In animals miRNAs more often have only partly the right sequence of nucleotides to bond with the target mRNA. The match-ups are imperfect. For partially complementary microRNAs to recognise their targets, nucleotides 2–7 of the miRNA (its 'seed region') still have to be perfectly complementary. Animal miRNAs inhibit protein translation of the target mRNA (this exists in plants as well but is less common). MicroRNAs that are partially complementary to a target can also speed up deadenylation, causing mRNAs to be degraded sooner. While degradation of miRNA-targeted mRNA is well documented, whether or not translational repression is accomplished through mRNA degradation, translational inhibition, or a combination of the two is hotly debated. Recent work on miR-430 shows that translational repression is caused by the disruption of translation initiation, independent of mRNA deadenylation.

miRNAs occasionally also cause histone modification and DNA methylation of promoter sites, which affects the expression of target genes.

Nine mechanisms of miRNA action are described and assemled in a unified mathematical model:

1. Cap-40S initiation inhibition;
2. 60S Ribosomal unit joining inhibition;
3. Elongation inhibition;
4. Ribosome drop-off (premature termination);
5. Co-translational nascent protein degradation;
6. Sequestration in P-bodies;
7. mRNA Decay (destabilisation);
8. mRNA Cleavage;
9. Transcriptional inhibition through microRNA-mediated chromatin reorganization following by gene silencing.

It is often impossible to discern these mechanisms using the experimental data about stationary reaction rates. Nevertheless, they are differentiated in dynamics and have different kinetic signatures.

Unlike plant microRNAs, the animal microRNAs target a diverse set of genes. However, genes involved in functions common to all cells, such as gene expression, have relatively fewer microRNA target sites and seem to be under selection to avoid targeting by microRNAs.

dsRNA can also activate gene expression, a mechanism that has been termed "small RNA-induced gene activation" or RNAa. dsRNAs targeting gene promoters can induce potent transcriptional activation of associated genes. This was demonstrated in human cells using synthetic dsRNAs termed small activating RNAs (saRNAs), but has also been demonstrated for endogenous microRNA.

Interactions between microRNAs and complementary sequences on genes and even pseudogenes that share sequence homology are thought to be a back channel of communication regulating expression levels between paralogous genes. Given the name "competing endogenous RNAs" (ceRNAs), these microRNAs bind to "microRNA response elements" on genes and pseudogenes and may provide another explanation for the persistence of non-coding DNA.