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Team Finds Function for Small Peptides Produced From Non-Coding RNA in Fruit Flies

By Andrea Anderson

NEW YORK (GenomeWeb News) – A study appearing online today in Science is providing evidence that a handful of small peptides produces from an apparently non-coding RNA can control the activity of a transcription factor during fruit fly development.

Japanese and French researchers looked at how mutating a small open reading frame called polished rice, or pri, alters fruit fly development. Their findings suggest four short peptides produced from pri interact with a transcription factor known as Shavenbaby, controlling its activity. Based on these findings, they say, it seems likely that at least some other non-coding transcripts code for puny peptides with important functions as well.

"We believe that — including during embryogenesis — free peptides are likely to control other transcriptional programs as well, which are Shavenbaby independent," co-corresponding author Francois Payre, a researcher affiliated with the University of Toulouse and the French National Center for Biological Research, told GenomeWeb Daily News. "It's likely that those peptides are re-used in different transcriptional programs during different stages of development."

Despite the fact that protein-coding sequences represent a fairly small portion of the eukaryotic genome, mounting evidence suggests much of the genome is transcribed. And at least some non-coding transcripts are transcribed into short peptides, the researchers explained, leading to speculation that some small open reading frames, or sORFs, have unappreciated functions in the cell.

"[T]here is growing evidence that the sORFs present in some ncRNAs are actually translated into small peptides, the abundance of which is probably greatly underestimated," they wrote. "Whereas sORF-encoded peptides may represent an overlooked repertoire of bioactive molecules, their functions, and the mechanisms by which they operate are largely unknown."

For the current study, Payre and his co-workers focused four such peptides encoded by sORFs in the Drosophila gene pri. Although Pri peptides are just 11 to 32 amino acids long, they noted, past studies suggest embryos missing the pri gene have development defects.

To explore this further, the team looked at how pri mutations altered fruit fly embryo development — particularly the formation of characteristic cell outgrowths called trichomes.

The team's findings suggest trichome defects that occur in the absence of pri actually reflect interactions between Pri peptides and the transcription factor Shavenbaby, or Svb.

In particular, their findings indicate that the presence of Pri peptides corresponds to the formation of a truncated version of Svb that acts as an activator rather than a repressor.

Without such peptides, though, Svb apparently remains repressive, inhibiting normal trichome formation. Moreover, the researchers found that Pri peptides seem to be linked to subtle change in Svb's location within the cell.

"All the four different small peptides are sharing a very highly conserved short peptide sequence," Payre said. "We don't know why there are the four different small ORFs, but we came to the conclusion that the peptides are very similar between the four ORFs and they are, in vivo, playing the same role."

Pri peptides likely aren't the only functional peptides produced from "non-coding" transcripts, Payre argued, noting that the threshold used to define protein-coding genes during genome annotation likely misses some authentic coding sequences, as do microarray studies focusing on predicted genes. And, researchers explained, that suggests more of the RNA transcribed from fruit fly and other eukaryotic genomes might be functional than currently realized.

"Future functional analyses should elucidate how small peptides encoded by transcripts improperly termed ncRNAs contribute to various biological processes including development and differentiation," the researchers concluded.

The team plans to look for more small peptides in the fruit fly and other cell types. Although such efforts are complicated by the fact that these peptides are often unstable and difficult to detect, Payre noted, he and his collaborators are exploring ways to better distinguish between these peptides and degradation products that are also detected by mass spectrometry.

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