Published online 15 July 2010 | Nature | doi:10.1038/news.2010.356

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Mystery RNA spawns gene-activating peptides

Short peptides that regulate fruitfly development are produced from 'junk' RNA.

Fruit Fly (Drosophila melanogaster)A type of RNA that was thought to be non-functional regulates development in fruitflies.Albert Lleal/Minden Pictures/FLPA

Some so-called 'non-coding' pieces of RNA may actually encode short proteins that regulate genes, researchers have found.

Protein-coding messenger RNA molecules serve as templates for the production of proteins in cells, while a variety of non-coding RNA molecules are known that do not produce protein but are known either to regulate gene expression directly or to carry out other functions in the cell. But many researchers have questioned whether the rest of the apparently non-coding RNA made in cells serves any function at all.

Some argue that the many RNAs observed to be transcribed from the vast stretches of non-coding DNA between known genes are merely artefacts of the high-throughput technology used to detect RNAs on a genome-wide scale (see 'Existence of RNA dark matter in doubt'). Others believe they are merely junk — the accidental by-products of the process that transcribes RNA from a DNA template.

“We missed microRNA for decades — maybe we missed 'micropeptides' for even longer.”


But now Yuji Kageyama at the Okazaki Institute for Integrative Biology in Japan and his colleagues have found one such 'non-coding' RNA that does in fact code for several short chains of amino acids, or peptides, that act to regulate fruitfly development. Their discovery, published today in Science, suggests that more of these mysterious RNA molecules could produce peptides too small to be considered true proteins but which nonetheless carry out important functions within cells1.

This finding has echoes of the paradigm-changing discovery of the small non-coding RNAs called microRNAs, which have direct gene-regulatory functions. "This might be something very big," says Claude Desplan, a developmental biologist at New York University who was not involved in the study. "We missed microRNA for decades — maybe we missed 'micropeptides' for even longer."

The itsy-bitsy protein

In scans of the genome, a DNA sequence is generally not considered potentially protein-coding unless it can encode a string of more than 100 amino acids. And although some short peptides carry out important biological functions, such as signaling between brain cells, these peptides are usually fragments chipped off larger proteins.

Kageyama and his colleagues have now found an RNA that directly codes for four peptides, ranging in size from 11 to 32 amino acids long. This RNA is produced from a gene called polished rice, so-named because the embryos of flies with a mutation in the polished rice gene lack the hairs that characteristically decorate the surface of the fruitfly embryo (which resembles a grain of rice to the naked eye).

The team found that the polished rice peptides trigger the truncation of a protein called Shavenbaby, which regulates the development of the hairs. This shorter form of the Shavenbaby protein activates the expression of genes needed for hair growth.

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Short peptides could be lurking virtually anywhere in the genome, says Desplan. Sequence analysis suggests that DNA regions capable of encoding tiny peptides exist in front of many protein-coding genes, but few researchers believe that these regions are doing anything useful, he adds.

It should be possible to scan the genome for sequences encoding peptides shorter than 100 amino acids, says Mark Gerstein, a computational biologist at Yale University in New Haven, Connecticut, but sorting through the many 'hits' to determine which are functional is likely to be much more difficult.

Meanwhile, Gerstein notes that the polished rice peptides could also have implications for how we view pseudogenes, which have long been thought to be defunct relics of protein-coding genes. Pseudogenes often contain many signals that would stop protein synthesis and, as a result, could only encode short amino-acid chains. "Maybe this would provide a new way for pseudogenes to have some sort of function," he says. 

  • References

    1. Kondo, T. et al. Science 329, 336-339 (2010). | Article | ChemPort |
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