PIWI-interacting RNAs: from generation to transgenerational epigenetics

Key Points PIWI-interacting RNAs (piRNAs) are made from dedicated precursor transcripts that are transcribed from specialized loci. piRNA biogenesis from their precursors involves at least three different steps: first, the 5′ end is created by an endonuclease; second, the piRNA intermediate is loaded into a PIWI protein; and third, the 3′ end is trimmed and modified. Target selection by PIWI–piRNA complexes may depend on perfect or near perfect base-pairing interactions — for example, as occurs in Drosophila melanogaster and mice — or on interactions involving substantial mismatches, as occurs in Caenorhabditis elegans . PIWI proteins can trigger changes to the chromatin of their target loci. The exact mechanisms are thus far still not clear but bear similarities to the RNAi-heterochromatin pathway of fission yeast. The heterochromatin changes imposed by PIWI proteins can be inherited stably across generations. In some cases, maintenance of this silencing can occur in absence of further PIWI pathway activity. Changes to the chromatin structure of PIWI targets may convert such targets into piRNA-producing loci. In such cases, transcripts from these targets are efficiently routed into piRNA biogenesis pathways. PIWI-interacting RNAs (piRNAs) have important roles in various species, particularly in silencing transposons in the germ line. This Review describes our latest understanding of various steps in this process, from the specification of piRNA-producing loci to piRNA processing and nuclear effector functions, including a role in transgenerational epigenetic inheritance. Small-RNA-guided gene regulation is a recurring theme in biology. Animal germ cells are characterized by an intriguing small-RNA-mediated gene-silencing mechanism known as the PIWI pathway. For a long time, both the biogenesis of PIWI-interacting RNAs (piRNAs) as well as their mode of gene silencing has remained elusive. A recent body of work is shedding more light on both aspects and implicates PIWI in the establishment of transgenerational epigenetic states. In fact, the epigenetic states imposed by PIWI on targets may actually drive piRNA production itself. These findings start to couple small RNA biogenesis with small-RNA-mediated epigenetics.