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The widespread regulation of microRNA biogenesis, function and decay

Key Points

  • MicroRNAs (miRNAs) are a large family of post-transcriptional regulators of gene expression that control many developmental and cellular processes in eukaryotic organisms. Recent research indicates that miRNA regulators themselves are subject to sophisticated control at the levels of miRNA metabolism and function.

  • Transcription of miRNA genes is regulated similarly to that of protein-coding genes, and is a major level of control responsible for tissue-specific or development-specific expression. miRNAs are uniquely suited to participate in autoregulatory feedback circuits owing to their potential to directly repress mRNAs that encode factors involved in miRNA synthesis.

  • miRNA precursors are processed to mature miRNAs in two steps involving the RNase III family enzymes Drosha and Dicer. These maturation steps are subjects of intricate regulation (either positive or negative) by protein factors that either interact with Drosha or Dicer, or bind to miRNA precursors. Many regulators affect the processing of a broad range of miRNAs, indicating that they can modulate expression of entire gene networks.

  • Many miRNA precursors undergo editing by adenosine deaminases that catalyse the conversion of adenosine to inosine in dsRNA segments, altering the base-pairing and structural properties of transcripts. These modifications can affect miRNA processing and can also change properties of mature miRNAs.

  • miRNAs function in association with argonaute and glycine-tryptophan protein of 182 kDa (GW182) proteins, which are the main components of the miRNA-induced silencing complex (miRISC). As part of the miRISC, miRNAs base-pair to target mRNAs and induce their translational repression or deadenylation and degradation.

  • miRISCs interact with many additional factors that are required for miRNA function or for modulation. The mode of action for most of the accessory proteins remains unknown. Argonaute and GW182 proteins, and also some accessory factors, are subject to post-translational modifications that may regulate their activity.

  • The activity of miRISCs interacting with the mRNA 3′-UTR can be modulated by RNA-binding proteins interacting with the same mRNA. The same RNA-binding protein can, depending on the mRNA or cellular context, either prevent or activate miRISC repression.

  • It is generally thought that miRNAs are highly stable molecules. However, in some cell types, in particular in neurons, miRNAs decay very rapidly and their turnover is dependent on neuronal activity. The stability of mature miRNAs may be regulated by the untemplated addition of adenosine or uracil residues to the miRNA 3′ end.

  • miRNA repression may involve specific cellular structures or compartments such as processing bodies or multivesicular bodies. In neurons, selected miRNAs are enriched at distal sites in dendrites, and evidence exists to suggest that synaptic stimulation is accompanied by reactivation of mRNAs targeted by miRNAs at dendritic spines.

Abstract

MicroRNAs (miRNAs) are a large family of post-transcriptional regulators of gene expression that are 21 nucleotides in length and control many developmental and cellular processes in eukaryotic organisms. Research during the past decade has identified major factors participating in miRNA biogenesis and has established basic principles of miRNA function. More recently, it has become apparent that miRNA regulators themselves are subject to sophisticated control. Many reports over the past few years have reported the regulation of miRNA metabolism and function by a range of mechanisms involving numerous protein–protein and protein–RNA interactions. Such regulation has an important role in the context-specific functions of miRNAs.

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Figure 1: Regulators of microRNA processing.
Figure 2: Modification at the 3′ end of microRNAs regulates stability.
Figure 3: Interplay between RBPs and miRISCs at the mRNA 3′-UTR.

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Acknowledgements

We thank the members of the W.F. group for valuable discussion and comments on the manuscript. J.K. is a recipient of an EMBO Fellowship. I.L. is supported by Deutsche Forschungsgemeinschaft (DFG). The Friedrich Miescher Institute is supported by the Novartis Research Foundation. Research by W.F. is also supported by the EC FP6 Program “Sirocco”.

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Supplementary Table 1

Regulators of miRNA processing and function (PDF 320 kb)

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Glossary

Deadenylation

The removal of the poly(A) tail from the mRNA 3′ end. Deadenylation is the first step in mRNA decay, and is generally followed by removal of the m7G cap (the 7-methylguanosine-triphosphate structure at the 5′ end of mRNAs, which promotes their translation and protects them from degradation) and exonucleolytic 5′ to 3′ degradation of mRNA. Deadenylation is mainly mediated by the CAF1–CCR4 deadenylase complex.

Seed sequence

Nucleotide positions 2–8 from the 5′ end of the microRNA, which generally perfectly base-pair with target mRNA, and are important for defining the target repertoire of a microRNA.

Allosteric regulation

A mechanism by which an event at one region in a protein causes an effect at another site.

RNP

(Ribonucleoprotein). A complex of RNA and proteins. In the case of mRNPs the complex assembles on mRNA; in the case of miRNPs (also known as microRNA-induced silencing complexes), this involves microRNAs instead.

3′-UTR

The 3′-UTR controls many aspects of mRNA metabolism, such as transport, localization, efficiency of translation and stability. 3′-UTRs can extend over several kilobases and generally contain binding sites for various regulatory proteins and microRNAs allowing dynamic and combinatorial regulation.

CLIP

(Crosslinking immunoprecipitation). CLIP technology facilitates the identification and sequencing of short RNA regions associating with RNA-binding proteins or with microRNA-induced silencing complexes in intact cells.

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Krol, J., Loedige, I. & Filipowicz, W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 11, 597–610 (2010). https://doi.org/10.1038/nrg2843

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