Piwi Proteins and piRNAs step onto the systems biology stage

Animal germ cells are totipotent because they maintain a highly unique and specialized epigenetic state for its genome. To accomplish this, germ cells express a rich repertoire of specialized RNA-binding protein complexes such as the Piwi proteins and Piwi-interacting RNAs (piRNAs): a germ-cell branch of the RNA interference (RNAi) phenomenon which includes microRNA and endogenous small interfering RNA pathways. Piwi proteins and piRNAs are deeply conserved in animal evolution and play essential roles in fertility and regeneration. Molecular mechanisms for how these ribonucleoproteins act upon the transcriptome and genome are only now coming to light with the application of systems-wide approaches in both invertebrates and vertebrates. Systems biology studies on invertebrates have revealed that transcriptional and heritable silencing is a main mechanism driven by Piwi proteins and piRNA complexes. In vertebrates, Piwi-targeting mechanisms and piRNA biogenesis have progressed, while the discovery that the nuclease activity of Piwi protein is essential for vertebrate germ cell development but not completely required in invertebrates highlights the many complexities of this pathway in different animals. This review recounts how recent systems-wide approaches have rapidly accelerated our appreciation for the broad reach of the Piwi pathway on germline genome regulation and what questions facing the field await to be unraveled.