PIWI-interacting small RNAs: the vanguard of genome defence

Key Points

  • PIWI-interacting RNAs (piRNAs) are a distinct class of small non-coding RNAs that protect the integrity of the genome by silencing transposable elements in both germline and gonadal somatic cells. There are thousands of piRNA sequences in the genome and most reside in regions defined as piRNA clusters.

  • The pathways that drive the biogenesis of piRNAs are distinct from those that produce other small non-coding RNAs, including endogenous small interfering RNAs and microRNAs. piRNAs can arise from both a primary processing pathway and an amplifying, 'ping-pong' cycle that further refines the piRNA pool to ensure an effective defence against transposons.

  • piRNAs associate with PIWI proteins to form a piRNA-induced silencing complex (piRISC). Efficient piRNA-mediated silencing also requires association of several Tudor-domain proteins with PIWI proteins, as well as other non-Tudor-domain proteins.

  • There is emerging evidence that some piRNAs may also target protein-coding genes in both the germ line and the soma. In addition, piRNAs affect chromatin structure and transcription through effects on de novo methylation at loci containing transposable elements.

  • piRNAs localize to granular cytoplasmic bodies, where piRNA production and processing seems to take place. Although these show proximity to other mRNA processing bodies, the functional significance of this is not yet clear.

Abstract

PIWI-interacting RNAs (piRNAs) are a distinct class of small non-coding RNAs that form the piRNA-induced silencing complex (piRISC) in the germ line of many animal species. The piRISC protects the integrity of the genome from invasion by 'genomic parasites' — transposable elements — by silencing them. Owing to their limited expression in gonads and their sequence diversity, piRNAs have been the most mysterious class of small non-coding RNAs regulating RNA silencing. Now, much progress is being made into our understanding of their biogenesis and molecular functions, including the specific subcellular compartmentalization of the piRNA pathway in granular cytoplasmic bodies.

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Figure 1: Biogenesis of small RNAs in mammals.
Figure 2: Putative roles for piRNAs during silencing of protein-coding genes.
Figure 3: Two pathways for piRNA biogenesis.
Figure 4: PIWI and Tudor proteins regulate the piRNA pathway.
Figure 5: piRNA biogenesis takes place in cellular bodies.

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Acknowledgements

We thank H. Siomi, A. Nagao, A. Webster, N. Perkins and I. Olovnikov for comments on the manuscript. The work in the laboratory of M.C.S. is supported by Ministry of Education, Culture, Sports, Science and Technology (MEXT) grants to K.S. and M.C.S. M.C.S. is supported by the Core Research for Evolutional Science and Technology (CREST) programme of the Japan Science and Technology Agency (JST). The work in the laboratory of A.A.A. is supported by the US National Institutes of Health (grants DP2 OD007371A and R00 HD057233-02 to A.A.A.) and the Ellison Medical Foundation.

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Morphogen

A signalling molecule that provides positional information to cells by forming a concentration gradient across the developmental field, and elicits multiple different cellular responses to specify cell fates in a concentration-dependent manner.

Maternal–zygotic transition

A developmental switch during embryogenesis from control by maternally provided gene products to control by zygotically provided gene products. During this transition, embryonic transcription is initiated and many maternal products are degraded.

Pachytene stage

A stage in meiotic prophase when homologous chromosomes are completely paired and chromosomal crossover occurs.

Phasing

An endonucleolytic processing pattern with an equal periodicity. Small interfering RNAs are endonucleolytically processed (or 'diced') by Dicer from individual precursors at certain intervals to produce a typical size of 21 nucleotides. Dicer acts as a 'ruler' during processing.

Tudor domain

A conserved protein motif typically consisting of 50 amino-acid residues. It is commonly found in proteins, such as RNA-binding proteins. Some Tudor domains specifically recognize and bind symmetrically dimethylated arginines.

Hypervariable antibody repertoire

The antibody specificities that can potentially be produced by an individual. A huge repertoire of different antibodies is generated in a single individual.

Germline granule

A specialized electron-dense structure that comprises particular RNAs and proteins that are indispensable for germline development. Vasa, an RNA helicase, is a well-characterized component of germline granules.

High mobility group box

(HMG-box). A protein domain involved in DNA binding that comprises 80 amino-acid residues that form three α-helices.

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Siomi, M., Sato, K., Pezic, D. et al. PIWI-interacting small RNAs: the vanguard of genome defence. Nat Rev Mol Cell Biol 12, 246–258 (2011). https://doi.org/10.1038/nrm3089

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