New class of small RNAs found

Piwi-interacting, or piRNAs, may play a role in developing sperm in mice

By | June 5, 2006

A newly revealed class of thousands of distinct small RNA molecules in mammals is common in developing mouse sperm, two research teams report in the June 4 online edition of Nature. Although the presence of these piRNAs in developing sperm suggests they play essential roles during the complex process of gamete formation, their genesis and function remain unclear. "If our experience with piRNAs is anything like that with microRNAs, you'll see a wave of discovery from a lot of people following up on these unknowns," study author Thomas Tuschl at Rockefeller University in New York told The Scientist. The researchers investigated Piwi proteins, which are important in germ cell development in invertebrates and mice. These molecules make up a subgroup within the Argonaute proteins, which microRNAs target to silence genes. Both groups purified, cloned and sequenced RNAs associated with mouse testes immunoprecipitates of ribonucleoprotein complexes incorporating a Piwi protein. Tuschl and his colleagues looked at ones containing MILI, while Gregory Hannon at Cold Spring Harbor Laboratory in New York and his collaborators analyzed those with MIWI. While microRNAs are 21 to 23 nucleotides long, both groups discovered RNA molecules between 26 to 31 nucleotides long in their immunoprecipitates. Northern blotting revealed these single-stranded RNAs were linked with Piwi and not other Argonaute proteins, Hannon's group reported. Both groups dubbed these Piwi-interacting nucleotides, or piRNAs. "MILI binds to slightly smaller size piRNAs than MIWI," Hannon told The Scientist. Both groups found roughly 90% of piRNAs began with uracil, a trait seen in other small RNA molecules. Hannon and his colleagues discovered 52,934 candidate piRNAs in mouse testes, 52,099 in human and 47,024 in rat. In these species, most piRNAs clustered into relatively small number of loci, with about 100 major clusters in mice. This clustering suggests multiple piRNAs are processed from long transcripts, Tuschl said. Unlike microRNAs and short interfering RNAs (siRNAs), both groups suggested piRNAs might originate from single-stranded and not double-stranded RNA precursors. "PiRNAs only map to one strand of the genome," Tuschl said. Mouse piRNA sequences are well-conserved when compared with the closely related rat genome, but are poorly conserved between more distant species, Tuschl and his colleagues reported. Still, the vast majority of large mouse piRNA clusters are found in the same chromosomal positions in humans and rats. "They seem to localize to chromosomal landmarks of some sort. This strongly suggests they might have something to do with chromosome biology," Hannon said. PiRNAs appear less abundant in humans than in mice, Tuschl added. "Maybe in humans RNA-binding proteins replace some of the functions of large sets of piRNAs, assuming the function of piRNAs is to recognize complement messenger RNAs," he speculated. "RNA-binding proteins are one of the biggest classes of proteins in the human genome." Both groups used northern blotting to find piRNAs present in mouse germ cells, specifically accumulating at the onset of meiosis and lost before the production of mature sperm. This corresponds to when all three Piwi proteins are expressed in the mouse. "We only saw piRNAs in human testes or mouse testes," Tuschl said. They may be expressed in developing ovaries, he added. "There's a huge, final, rapid burst of these piRNAs just before we have the final burst of transcription before the end of meiosis in spermatids," Stephen Krawetz at Wayne State University in Detroit, not a co-author, told The Scientist. "So it would be interesting to see whether piRNAs involved in modulating that transcription or the storage of the RNAs." Future experiments should investigate what proteins are connected with Piwi-linked ribonucleoprotein complexes to see how piRNAs relate to known processes, Hannon said. Researchers may want to see what the piRNA expression profiles are like in Piwi-knockout animals, Minoo Rassoulzadegan at the University of Nice in France, who did not participate in the study, told The Scientist. Charles Q. Choi Links within this article A. Aravin et al. "A novel class of small RNAs bind to MILI protein in mouse testes." Nature, published online June 4, 2006. A. Girard et al. "A germline-specific class of small RNAs binds mammalian Piwi proteins." Nature, published online June 4, 2006. J.M. Perkel. "MicroRNAs assume a developmental role." The Scientist, April 1, 2006. Thomas Tuschl Gregory Hannon Stephen Krawetz Minoo Rassoulzadegan

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