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  • Review Article
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Biological principles of microRNA-mediated regulation: shared themes amid diversity

Nature Reviews Genetics volume 9, pages 831–842 (2008)Cite this article

Key Points

  • MicroRNAs (miRNAs) are ∼22-nucleotide regulatory RNAs derived from endogenous transcripts containing inverted repeats. Their predominant function is to repress the activity of cellular target transcripts.

  • In plants, most miRNAs are highly complementary to their targets and can cleave them; however, plant miRNAs can also inhibit the translation of highly complementary targets. In animals, miRNAs identify most of their targets through Watson–Crick complementary pairing (nucleotides 2–8 of the miRNA (the 'seed') pair with the target), and induce target destabilization and/or translational inhibition.

  • The phenotypic requirements of most plant miRNAs, along with at least some animal miRNAs, seem to be mediated by the strong repression of one or a few important targets. For such miRNA genetic switches, the loss of miRNA-mediated regulation of individual target genes can lead to morphological or behavioural abnormalities.

  • The regulation of a target by a miRNA could be relatively subtle and still have a substantial phenotypic impact, if the modulation of the target over a narrow range alters the target's output. Targets regulated in this manner include 'tuning', 'thresholding' and 'de-noising' targets.

  • Conserved seven-nucleotide-seed matches, along with transcriptome and proteome analyses, have revealed that animal miRNAs have many (often hundreds) of targets. This might allow miRNAs to have a broad impact on the spatial or temporal identity of a cell. In other cases, however, most of these target interactions might be of minimal detectable consequence; detailed genetic studies are required to distinguish these possibilities.

  • There is evidence, mostly from animals, that miRNA-mediated repression is reversible. Therefore, antagonizing miRNA activity allows the reuse of repressed target messages under conditions in which this is desirable.

  • miRNA dysfunction may contribute to human disease in myriad ways. Ectopic miRNA activity or the loss of miRNA-binding sites could lead to abnormal levels of one or many transcripts. On the other hand, miRNA loss or gain of miRNA-mediated regulation could lead to the inappropriate silencing of one or many transcripts.

Abstract

Regulation of gene activity by microRNAs is critical to myriad aspects of eukaryotic development and physiology. Amidst an extensive regulatory web that is predicted to involve thousands of transcripts, emergent themes are now beginning to illustrate how microRNAs have been incorporated into diverse settings. These include potent inhibition of individual key targets, fine-tuning of target activity, the coordinated regulation of target batteries, and the reversibility of some aspects of microRNA-mediated repression. Such themes may reflect some of the inherent advantages of exploiting microRNA control in biological circuits, and provide insight into the consequences of microRNA dysfunction in disease.

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Figure 1: Classifying microRNA (miRNA) activities and functions.
Figure 2: Consequences of microRNA (miRNA) loss- or gain-of-function for cell state.
Figure 3: Multiple microRNA (miRNA) genetic switches in the nematode heterochronic pathway.
Figure 4: Configurations of microRNA (miRNA)–target networks.
Figure 5: Antagonism of microRNA (miRNA)-mediated repression.

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Acknowledgements

We apologize to the many researchers whose findings were not covered in this Review owing to space limitations. This work was supported by grants from the V Foundation for Cancer Research, the Sidney Kimmel Cancer Foundation, the Alfred Bressler Scholars Fund and the US National Institutes of Health (R01-GM083300).

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  1. Department of Developmental Biology, Sloan–Kettering Institute, 521 Rockefeller Research Labs, 1275 York Avenue, Box 252, New York, 10065, New York, USA

    Alex S. Flynt & Eric C. Lai

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Correspondence to Eric C. Lai.

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FURTHER INFORMATION

TargetScan

Glossary

Argonaute proteins

A family of proteins with PAZ and PIWI domains that directly bind specific small RNAs (including miRNAs, siRNAs and piRNAs). After binding, the small RNA guides the Argonaute, along with its associated protein complex, to regulatory targets.

Genetic drift

Changes in allele frequency or nucleotide identity that occur entirely by chance.

Epistasis analysis

A genetic-interaction test that is applied when mutations in two genes yield different phenotypes with respect to a common biological process. One of the genes is said to be epistastic if the phenotype of the double mutant resembles that of the single mutant, as opposed to being intermediate.

Heterochronic gene

A gene that determines an organism's stage-specific temporal state during its development.

Imaginal discs

Tissues that, in holometabolous insects such as D. melanogaster, will give rise to the adult structures during metamorphosis.

Notch

A transmembrane receptor that coordinates a cell–cell signalling cascade that is fundamental to the specification of diverse animal cell fates.

Canalization

The capacity of individuals within a species to yield similar phenotypic traits despite genetic and/or environmental variability.

Drosha and Dicer

RNAse III enzymes that catalyse nuclear and cytoplasmic cleavage, respectively, of animal miRNA precursors. Plants lack Drosha, and a Dicer homologue called Dicer-like 1 seems to execute both cleavage events in the nucleus during miRNA maturation. Various animal and plant Dicers are also involved in small interfering RNA biogenesis.

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Flynt, A., Lai, E. Biological principles of microRNA-mediated regulation: shared themes amid diversity. Nat Rev Genet 9, 831–842 (2008). https://doi.org/10.1038/nrg2455

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