The biogenesis and function of PIWI proteins and piRNAs: progress and prospect

Abstract

The evolutionarily conserved Argonaute/PIWI (AGO/PIWI, also known as PAZ-PIWI domain or PPD) family of proteins is crucial for the biogenesis and function of small noncoding RNAs (ncRNAs). This family can be divided into AGO and PIWI subfamilies. The AGO proteins are ubiquitously present in diverse tissues. They bind to small interfering RNAs (siRNAs) and microRNAs (miRNAs). In contrast, the PIWI proteins are predominantly present in the germline and associate with a novel class of small RNAs known as PIWI-interacting RNAs (piRNAs). Tens of thousands of piRNA species, typically 24-32 nucleotide (nt) long, have been found in mammals, zebrafish, and Drosophila. Most piRNAs appear to be generated from a small number of long single-stranded RNA precursors that are often encoded by repetitive intergenic sequences in the genome. PIWI proteins play crucial roles during germline development and gametogenesis of many metazoan species, from germline determination and germline stem cell (GSC) maintenance to meiosis, spermiogenesis, and transposon silencing. These diverse functions may involve piRNAs and may be achieved via novel mechanisms of epigenetic and posttranscriptional regulation.

Figure 1

The role PIWI-like proteins during mammalian spermatogenesis. A schematic drawing of mouse spermatogenesis on a time coordinate, with MILI, MIWI, and MIWI2 expression periods indicated.

Figure 2

The 3-D structure of a ternary complex of the wild-type Thermus thermophilus AGO in complex with aDNA-piRNA heteroduplex. Red: DNA; blue: RNA. Adopted from Wang et al. 2008.

Figure 3

The Biogenesis and function of piRNAs. piRNAs are processed from long precursors encoded by long primary transcripts. A. Often piRNAs cluster to arrays that appear to bi-directionally transcribed, while less often are primary transcripts derived from one strand. B. The clusters are transcribed as long transcripts that go through primary processing to give rise to mature piRNAs, the mechanism of primary processing is not understood. C. piRNAs are believed to be vectors for transposon mRNA regulation, which leads potentially to degradation. D. At the same time, post-transcriptional amplification leads to more mature piRNAs (see figure 4 and text). E. several lines of evidence show that PIWI proteins, presumably through piRNAs lead to epigenetic repression of transposon encoding regions (red arrow). F. Other epigenetic functions of PIWI-proteins may exist, at least in Drosophila more than one line of evidence indicate that PIWI-proteins have a role in telomere length maintenance and epigenetic control. The epigenetic control appears to involve piRNAs as sequence recognition molecules. G. Evidence for a role of piRNAs in translational control and other functions exists but remain to be stringently tested.

Figure 4

The Ping-Pong model for piRNA amplification in Drosophila. Mammalian post-transcriptional amplification appears to be a similar process. See text for detaied description of the model.