In the last decade, few areas of biology have been transformed as thoroughly as RNA molecular biology. This transformation has occurred along many fronts, as detailed in this issue, but one of the most significant advances has been the discovery of small (~20−30 nucleotide [nt]) noncoding RNAs that regulate genes and genomes. This regulation can occur at some of the most important levels of genome function, including chromatin structure, chromosome segregation, transcription, RNA processing, RNA stability, and translation. The effects of small RNAs on gene expression and control are generally inhibitory, and the corresponding regulatory mechanisms are therefore collectively subsumed under the heading of RNA silencing. The central theme that runs throughout is that the small RNAs serve as specificity factors that direct bound effector proteins to target nucleic acid molecules via base-pairing interactions. Invariably, the core component of the effector machinery is a member of the Argonaute protein superfamily. Because the small RNAs render the silencing machinery addressable in ways that can be predicted and in some cases controlled, the associated pathways have taken on great importance in practical and applied realms.
Although many classes of small RNAs have emerged, various aspects of their origins, structures, associated effector proteins, and biological roles have led to the general recognition of three main categories: short interfering RNAs (siRNAs), microRNAs (miRNAs), and piwi-interacting RNAs (piRNAs). These RNAs are only known to be present in eukaryotes, although the Argonaute proteins that function in eukaryotic silencing can also be found in scattered bacterial and archaeal species. The boundaries between the various small RNA classes are becoming increasingly difficult to discern as described in more detail below, but nonetheless some distinctions persist. siRNAs and miRNAs are the most broadly distributed in both phylogenetic and physiological terms and are characterized by the double-stranded nature of their precursors. In contrast, piRNAs are primarily found in animals, exert their functions most clearly in the germline, and derive from precursors that are poorly understood but appear to be single stranded (see Review by C.D. Malone and G. J. Hannon on page 656 of this issue). Most definitively, piRNAs and si/miRNAs associate with distinct subsets of effector proteins—siRNAs and miRNAs bind to members of the Ago clade of Argonaute proteins, whereas piRNAs bind to members of the Piwi clade.
This review will focus on siRNAs and miRNAs, with an emphasis on their biogenesis and silencing mechanisms. We will focus on developments over the last several years and will rely upon prior reviews to provide the reader with references to earlier discoveries in the field (also see Reviews in this issue by O. Voinnet on page 669, about the biological processes that are under siRNA and miRNA control in plants, and by C.D. Malone and G. J. Hannon on page 656, about piRNAs, Piwi proteins, and their roles in transposon control and genome defense). We will begin with the core aspects of the siRNA and miRNA pathways that are shared by both and then will discuss their unique features in turn.