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Emerging roles and functional mechanisms of PIWI-interacting RNAs

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A Publisher Correction to this article was published on 04 October 2022

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Abstract

PIWI-interacting RNAs (piRNAs) are a class of small non-coding RNAs that associate with proteins of the PIWI clade of the Argonaute family. First identified in animal germ line cells, piRNAs have essential roles in germ line development. The first function of PIWI–piRNA complexes to be described was the silencing of transposable elements, which is crucial for maintaining the integrity of the germ line genome. Later studies provided new insights into the functions of PIWI–piRNA complexes by demonstrating that they regulate protein-coding genes. Recent studies of piRNA biology, including in new model organisms such as golden hamsters, have deepened our understanding of both piRNA biogenesis and piRNA function. In this Review, we discuss the most recent advances in our understanding of piRNA biogenesis, the molecular mechanisms of piRNA function and the emerging roles of piRNAs in germ line development mainly in flies and mice, and in infertility, cancer and neurological diseases in humans.

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Fig. 1: piRNA transcription and biogenesis in Drosophila melanogaster ovaries.
Fig. 2: piRNA transcription and biogenesis in the mouse.
Fig. 3: piRNA-dependent transcriptional TE silencing.
Fig. 4: Mechanisms of action of piRNAs and PIWI proteins in protein-coding gene regulation.

Change history

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Acknowledgements

The authors apologize to those whose work has not been included due to space limitations. They are grateful to D. Ding from Tongji University for critically reading the manuscript and members of the M.-F.L. laboratory and the M.S. laboratory for assisting with manuscript preparation. This work was supported by grants from the National Key R&D Program of China (2021YFC2700200 and 2017YFA0504400), the National Natural Science Foundation of China (91940305, 31830109, 31821004, 31961133022, 91640201 and 32101037), the Chinese Academy of Sciences (Strategic Priority Research Program grant XDB19010203), the Science and Technology Commission of Shanghai Municipality (2017SHZDZX01, 19JC1410200, 21YF1452700, 21ZR1470500 and 17JC1420100), the Innovative Research Team of High-Level Local Universities in Shanghai (SHSMU- ZDCX20210902), the Foundation of Key Laboratory of Gene Engineering of the Ministry of Education of China, and the Young Elite Scientist Sponsorship Program of the China Association for Science and Technology (2021QNRC001), and by UMR9002 CNRS–University of Montpellier and grants from the French Agence Nationale de la Recherche (ANR-17-CE12-0011-01, ANR-19-CE12-0031 and ANR-21-CE12-0035-01), Fondation pour la Recherche Médicale, Fondation ARC and Labex EpiGenMed to M.S. and A.R.

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Glossary

PIWI

A subfamily of Argonaute family proteins that are primarily expressed in animal germ lines and have essential roles in animal germ line development. The name comes from the first identified member of the piwi gene family, the Drosophila melanogaster piwi (P-element-induced wimpy testis) gene.

Argonaute

A large protein family involved in small RNA-guided gene silencing. The eukaryotic Argonaute family can be divided into AGO-clade and PIWI-clade proteins. A third distant clade, known as WAGO, has evolved in Caenorhabditis elegans.

Transposable elements

(TEs). DNA sequences that can change their position within the genome and insert themselves into different sites in chromosomes, potentially resulting in genome rearrangement and gene dysregulation.

piRNA cluster

A specific genomic locus from which PIWI-interacting RNA (piRNA) precursor transcripts are transcribed. The vast majority of piRNAs are produced from piRNA clusters.

Ping-pong amplification

PIWI-interacting RNA (piRNA) processing pathway in which the cleavage of piRNA precursors is done by the endonuclease activity of a piRNA-guided PIWI protein. Ping-pong produces piRNAs in opposite orientation with a ten-nucleotide overlap.

Phasing

Also known as phased PIWI-interacting RNA (piRNA) processing, an endonucleolytic processing mechanism through which the endonuclease Zucchini cleaves piRNA precursor transcripts repeatedly without or with a short intervening sequence, leading to a trail of head-to-tail piRNAs.

Slicing

RNA cleavage by the RNase H-like catalytic activity of Argonaute family proteins. Slicing by a small RNA-guided Argonaute protein occurs on the target RNA between nucleotide 10 and nucleotide 11 from the 5′ end of the small RNA.

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Wang, X., Ramat, A., Simonelig, M. et al. Emerging roles and functional mechanisms of PIWI-interacting RNAs. Nat Rev Mol Cell Biol 24, 123–141 (2023). https://doi.org/10.1038/s41580-022-00528-0

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