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MIT's Kellis Finds Possible Genetic Switch in Dual-Direction DNA

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While biologists debate the idea that most noncoding RNA serves no real function in the genome, MIT's Manolis Kellis is busy finding function in the most unexpected places. In his latest work, he's located pairs of miRNAs expressed from the same double-stranded DNA that are both functional. "What we've found out now is that, in fact, for some miRNA genes, the antisense transcript gets processed into a mature miRNA, which itself has distinct functions," Kellis says. "Both directions of the DNA are coding for distinct functions."

Kellis' work, published in the January 1 issue of Genes & Development, found two such miRNA pairs in the fruit fly and eight pairs in the mouse. The research is important simply because "double duty nucleotides" have never been observed before in animals, Kellis says. He adds, "It's not just that you're trying to cram in additional function in a little space — it's that antisense miRNA, sense/antisense pairs, provide a natural mechanism for a genetic switch." 

Using a computational approach, he and his team searched sequence alignment data for evolutionarily conserved miRNA elements, and isolated several that appeared to be sense/antisense pairs. In predicting that their targets would be several Hox genes — these genes play a large role in controlling the positioning of body parts — they ran several follow-up functional assays. First, they successfully matched known sequencing reads to the in vivo miRNA transcript. Second, upon expressing the antisense miRNA in vivo, they found that the targeted Hox gene was repressed. Finally, a transgenic fly built to overexpress the antisense miRNA showed marked homeotic transformation — the transformation of one body part to another is a hallmark of Hox gene regulation gone awry. "The most surprising thing was that the antisense transcript, in fact, showed a homeotic transformation that is much, much more pronounced than the sense miRNA," says Kellis. He notes that when they overexpressed the sense miRNA, there was instead a very subtle effect.

Kellis believes that the sense/antisense pairs in the Hox cluster may contribute to maintaining this tightly regulated developmental circuit. There could be more of these kinds of pairs, providing in equal measure form and function, throughout a variety of genomes. "This is pretty exciting in the sense that it's not just a Drosophila-specific thing and it's not just a Hox-specific thing," Kellis says. "It may be a more general regulatory mechanism for animals."

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