RESEARCH HIGHLIGHTS

SMALL for a self-recognition mechanism that protects endogenous sequences from being silenced by piRNAs. This Transmitting silence mechanism is not known yet, but the authors suggest that it might involve a different type of AGO known through generations as CSR-1. Importantly, both groups found The Miska and Mello laboratorie­s exclusively in male and female that although PRG-1 initiates silenc- shed light on the silencing mecha- germlin­e cells along with endogenous ing, it is not necessary to maintain it nisms of Piwi-interacting RNAs piRNAs (which are 21 through generations; maintenance (piRNA­s) in Caenorhabditis elegans long (21U-RNAs)). depends on chromatin factors and and on how silencing triggered by To identify piRNA targets and the WAGO–22G-RNA pathway. both piRNAs and environmental RNA the mechanisms by which piRNAs Interestingly, when comparing the interference (RNAi) is transmitted act on their targets in C.elegans, both mechanisms underlying piRNA- through generations. groups used strains that carried a mediated silencing and environmental In C. elegans, the effectors of piRNA sensor — a GFP reporter RNAi, which are both transmitted RNAi are small interfering RNAs that contained a short sequence through generations, Miska and (siRNAs) that bind (AGO) complementary to an endogenous colleagues found that they converge proteins to direct them to their piRNA. Their studies indicated that on a common nuclear RNAi and targets. Primary siRNAs result from silencing requires PRG-1 but also chromatin pathway. Indeed, they the processing of food-derived or involves the generation of 22G-RNAs. identify histone H3 Lys9 methylation, injected double-stranded RNAs and Interestingly, these secondary factors and nuclear activate RNA-dependent RNA poly- siRNAs act on imperfectly comple- RNAi defective 2 (NRDE-2) as fac- merase to generate secondary siRNAs. mentary sites proximal to the piRNA tors required for transgenerational Secondary siRNAs are usually target site and function to silence inheritanc­e of both silencing triggers. 22 nucleotides long (22G-RNAs) and transcripts both at co-transcriptional These findings add to the under- acquired interact with worm-specific AGO and post-transcriptional levels. Thus, standing of the intricate mechanisms traits can be proteins (WAGOs) to silence their tar- piRNAs can initiate silencing through of and also provide an transmitted gets. Endogenous WAGO–22G‑RNA imperfect base-pair interactions, example of how acquired traits can through pathways silence many loci, yet how which increases the potential number be transmitted through generations. these pathways are triggered and how of targets for any given piRNA. Importantly, they show that once a generations transgenerational inheritance is main- Mello and colleagues also observed sequence is identified as foreign and tained remains controversial. that when single-copy transgenes silenced, an epigenetic memory is piRNAs function together with consisting of an endogenous germline created that silences the foreign gene Piwi proteins of the AGO superfamily gene fused to a foreign sequence were from one generation to the next. This to silence transposons in the germ inserted at a given chromosomal mode of permanent silencing, referred ­line. PRG-1 belongs to the site, they could be either expressed to as RNA-induced epigenetic silenc- Piwi family and is expressed or silenced depending on the length ing (RNAe), could have profound of the foreign sequence. They found implications for biological adaptation that silencing was permanent and and evolution, as well as for health. dependent on targeting of the foreign Kim Baumann sequence by WAGO–22G-RNAs. This suggests that PRG-1 scans ORIGINAL RESEARCH PAPERS Bagijn, M. P. et al. for foreign RNA sequences and Function, targets, and evolution of Caenorhabditis initiates WAGO-dependent silenc- elegans piRNAs. Science 14 Jun 2012 (doi:10.1126/ science.1220952) | Shirayama, M. et al. piRNAs ing in the germ line. In addition, initiate an epigenetic memory of nonself RNA in single-copy transgenes were never the C. elegans germline. Cell 150, 65–77 (2012) | silenced when inserted directly into a Lee, H.-C. et al. C. elegans piRNAs mediate the -wide surveillance of germline prg-1 mutant, indicating that PRG-1 transcripts. Cell 150, 78–87 (2012) | Ashe, A. et al. and piRNAs are essential for the initial piRNAs can trigger a multigenerational recognition of the foreign sequence. epigenetic memory in the germline of C. elegans. Cell 150, 88–99 (2012) Furthermore, they provided evidence MACMILLAN MEXICO

NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 13 | AUGUST 2012

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