Abstract
Distinguishing self from non-self plays a crucial role in safeguarding the germlines of metazoa from mobile DNA elements. Since their discovery less than a decade ago, Piwi-interacting RNAs (piRNAs) have been shown to repress transposable elements in the germline and, hence, have been at the forefront of research aimed at understanding the mechanisms that maintain germline integrity. More recently, roles for piRNAs in gene regulation have emerged. In this Review, we highlight recent advances made in understanding piRNA function, highlighting the divergent nature of piRNA biogenesis in different organisms, and discussing the mechanisms of piRNA action during transcriptional regulation and in transgenerational epigenetic inheritance.
Highlights
The discovery of small non-coding RNAs, including microRNAs and short interfering RNAs (Hamilton and Baulcombe, 1999; Lee et al, 1993; Reinhart et al, 2000) revolutionised our understanding of how gene expression is regulated
Loss of Piwi leads to loss of histone H3 lysine 9 trimethylation (H3K9me3) and an increase in Polymerase II (POL II) occupancy at transposable elements (Le Thomas et al, 2013; Sienski et al, 2012); and recruitment of the heterochromatin protein HP1 to a piRNA reporter subjected to transcriptional gene silencing (TGS) has been demonstrated (Le Thomas et al, 2013). These findings suggest a model for Piwi-mediated TGS in which Piwi translocates to the nucleus to potentially interact with nascent transcript or DNA at the target locus, which in turn leads to heterochromatin formation and transcriptional repression (Fig. 2A). piRISC-induced TGS requires the zinc-finger protein GTSF-1/Asterix, which likely directly interacts with Piwi and is required for establishment of H3K9 methylation (Donertas et al, 2013; Handler et al, 2013; Muerdter et al, 2013)
The establishment of this nuclear silencing downstream of piRNAs occurs by a mechanism that is very similar to the relatively wellcharacterised nuclear RNAi pathway acting in somatic tissues: a germline-specific nuclear Argonaute known as HRDE-1 binds secondary 22G-RNAs and likely functions in a manner that is analogous to the somatic nuclear RNAideficient 3 (NRDE-3) (Ashe et al, 2012; Buckley et al, 2012; Luteijn et al, 2012), shuttling into the nucleus and initiating H3K9me3 methylation and POL II stalling (Fig. 2C). piRNA-mediated TGS depends on NRDE-1, NRDE2 and NRDE-4, indicating that these are general rather than somarestricted nuclear small RNA pathway factors
Summary
The discovery of small non-coding RNAs, including microRNAs (miRNAs) and short interfering RNAs (siRNAs) (Hamilton and Baulcombe, 1999; Lee et al, 1993; Reinhart et al, 2000) revolutionised our understanding of how gene expression is regulated. Additional mechanisms of piRNA action, namely target mRNA deadenylation, have been reported, as they are implied in regulation of protein-coding gene expression rather than transposon silencing, we discuss these findings later when describing new evidence for non-transposon targets of piRNAs. Evidence for piRNA-mediated transcriptional silencing in D. melanogaster Several studies have explored the role of D. melanogaster Piwi in transcriptional gene silencing (TGS).
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