Gene regulation by microRNAs

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The role of small RNAs as key regulators of mRNA turnover and translation has been well established. Recent advances indicate that the small RNAs termed microRNAs play important roles in animal development and physiology. Cellular activities such as proliferation, morphogenesis, apoptosis and differentiation are regulated by microRNAs. The expression of various genes are regulated by microRNAs, and several microRNAs act in reciprocal negative feedback loops with protein factors to control cell fate decisions that are triggered by signal transduction activity. These observations implicate small RNAs as important mediators of gene regulation in response to cell–cell signaling. The mechanism by which microRNAs silence gene expression is post-transcriptional, possibly influencing the stability, compartmentalization and translation of mRNAs. This mechanism is an efficient means to regulate production of a diverse range of proteins.

Introduction

Although the role that proteins play in gene regulation is well understood, it has become clear that RNAs are also important gene regulatory factors. Small RNAs, including microRNAs (miRNAs) and short interfering RNAs (siRNAs), are components of an RNA-based mechanism of gene regulation found in eukaryotes. siRNAs are used throughout the Eukaryota to inhibit viruses and transposable elements. They also play a role in chromosome organization and in silencing the expression of protein-coding genes. The miRNA branch of RNA-based gene regulation is less widespread; miRNAs are found in plants and animals but are apparently absent in fungi. This review focuses upon recent advances in our understanding of miRNAs and their manifest functions in animal development and physiology.

Section snippets

MicroRNA biogenesis and mechanism

The number of miRNA genes found in sequenced animal species corresponds to approximately 0.5–1.5% of the total number of genes in their genomes (http://www.sanger.ac.uk/Software/Rfam/mirna/index.shtml). The fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans have, at the latest count, 78 and 114 miRNA genes, respectively. Humans have at least 326 miRNA genes. MicroRNAs are transcribed by RNA polymerase II, and the primary transcripts contain hairpin–loop domains that fold

What are the targets of miRNA regulation?

A major question about miRNAs concerns the extent of their regulation of animal genomes. Computational methods have been helpful in estimating this value. When the 3′ UTRs from sequenced mammalian genomes were aligned, sequences capable of forming 6–8 bp perfect duplexes with the 5′ ends of many human miRNAs were identified [18]. Given the frequency of 3′ UTR motifs with complementary miRNAs found, it was estimated that approximately 20 to 30% of all human genes are targets of miRNA regulation,

Biological regulation by miRNAs: global approaches

If 30% of the coding genome is repressed by miRNAs, then the breadth of regulated biological processes might be enormous. To address this issue, several groups have investigated the consequences of eliminating miRNA maturation by examining the phenotypes of Dicer mutant animals. Surprisingly, they have revealed rather focused deficits that suggest more specific roles for miRNAs. Knockout of mouse Dicer results in embryonic lethality, and conditional removal of Dicer from the embryonic limb

Biological regulation by miRNAs: single-gene approaches

Another method to determine the functions of miRNAs is to inactivate each miRNA individually (Table 1). Due to the small size of each gene, mutagenesis has been technically challenging, but recent progress has been forthcoming. As one would expect, specific miRNA genes have been found to be important for cell growth, morphogenesis and apoptosis. The largest Drosophila miRNA gene family, the miR-2 family, is required for the suppression of apoptosis during embryogenesis [32]. This observation

Conclusions

It is becoming clear that miRNAs play diverse regulatory roles in animal cells. They might use several mechanisms to repress gene expression, although it is still uncertain if these are related to each other. Cellular activities such as proliferation, morphogenesis, apoptosis and differentiation are regulated by miRNAs, and in some cases, upstream and downstream genes have been linked to the miRNAs. Several miRNAs have been found to act in reciprocal negative feedback loops with protein factors

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work has been supported by the National Institutes of Health.

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