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  • Review Article
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MicroRNAs and their targets: recognition, regulation and an emerging reciprocal relationship

Nature Reviews Genetics volume 13, pages 271–282 (2012)Cite this article

Subjects

Key Points

  • MicroRNAs (miRNAs) function as 21–24-nucleotide-long guides that regulate the expression of mRNAs containing complementary sequences.

  • Although plant miRNAs typically base-pair perfectly to target sites, animal miRNAs form imperfect duplexes with target sequences, complicating the ability to predict direct targets.

  • Numerous computational and experimental methods have been developed for studying miRNA target recognition and regulation.

  • In plants and animals, miRNAs usually repress target expression by inducing mRNA deadenylation and degradation or by inhibiting translation.

  • Many factors, including target site context, RNA-binding proteins and modifying enzymes, influence the ability of the miRNA complex to bind and regulate specific targets.

  • Base pairing between an miRNA and its target can influence the stability of the miRNA, resulting in increased miRNA levels in some cases and stimulated degradation in others.

  • Coding and non-coding RNAs can function as competing endogenous RNAs (ceRNAs) that bind miRNAs, sequestering them from binding and regulating other RNAs.

  • miRNA 'sponges' have been engineered to titrate specific miRNAs to study their functions in vivo.

  • The new understanding that miRNAs can both regulate and be regulated by target interactions raises many questions regarding the definition of a miRNA target and the functional outcome of miRNA targeting in vivo.

Abstract

MicroRNAs (miRNAs) have emerged as key gene regulators in diverse biological pathways. These small non-coding RNAs bind to target sequences in mRNAs, typically resulting in repressed gene expression. Several methods are now available for identifying miRNA target sites, but the mere presence of an miRNA-binding site is insufficient for predicting target regulation. Regulation of targets by miRNAs is subject to various levels of control, and recent developments have presented a new twist; targets can reciprocally control the level and function of miRNAs. This mutual regulation of miRNAs and target genes is challenging our understanding of the gene-regulatory role of miRNAs in vivo and has important implications for the use of these RNAs in therapeutic settings.

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Figure 1: miRNA biogenesis.
Figure 2: Examples of functional miRNA target sites.
Figure 3: Mechanisms of target regulation by miRNAs.
Figure 4: Regulation of miRNA-targeting efficiency.
Figure 5: Regulation of miRNA stability and function by target interactions.

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Acknowledgements

Research in this laboratory is supported by the US National Institutes of Health (GM071654), Keck and Peter Gruber Foundations.

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  1. Division of Biology, University of California, San Diego, La Jolla, California, USA

    Amy E. Pasquinelli

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  1. Amy E. Pasquinelli
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Glossary

miRNA-induced silencing complex

(miRISC). This is composed of the miRNA guide and the effector proteins, which minimally include Argonaute proteins. The complex recruits additional proteins to regulate the stability or translation of targeted mRNAs.

Crosslinking immunoprecipitation

(CLIP). A method used to isolate and identify sequences that are bound by specific RNA-binding proteins. CLIP of microRNA complex proteins, such as Argonaute, has been used to detect microRNA-induced silencing complex (miRISC)-binding sites on genome-wide scales.

GW182 proteins

Glycine–tryptophan repeat-containing proteins that interact with the microRNA-induced silencing complex (miRISC) to recruit proteins that mediate degradation or translational repression of target mRNAs. Also known as TNRC6A, TNRC6B and TNRC6C in vertebrates and AIN-1 and AIN-2 in Caenorhabditis elegans.

Fragile X mental retardation syndrome-related protein 1

(FXR1). An RNA-binding protein that can regulate the translation or stability of bound transcripts.

P bodies

Processing bodies, or P bodies, are cytoplasmic foci enriched for proteins that are involved in RNA degradation but that are devoid of translation factors. MicroRNAs, Argonaute and GW182 proteins also localize to P bodies, and silencing of some targets may occur in these structures.

Competing endogenous RNAs

(ceRNAs). Bind miRNA complexes, titrating them from other target RNAs. Long non-coding RNAs, pseudogene RNAs and mRNAs can compete with other RNAs for access to specific miRNA complexes, effectively diluting their activity.

Pseudogene

Relatives of protein-coding genes that can no longer be translated into functional gene products. In some cases, pseudogene RNAs are still transcribed but are then improperly processed or translated.

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Pasquinelli, A. MicroRNAs and their targets: recognition, regulation and an emerging reciprocal relationship. Nat Rev Genet 13, 271–282 (2012). https://doi.org/10.1038/nrg3162

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