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Looks Like a Gene, Talks Like a Gene: Rinn Elucidates New Class of LincRNAs

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John Rinn has been getting a lot of phone calls lately. As a key member of the team that discovered a new class of RNAs, Rinn has been talking with scores of researchers eager to understand what he found.

According to Rinn, the discovery started when he first stumbled upon an RNA he named HOTAIR. From a chromatin perspective, HOTAIR looked like a regular protein-coding gene — but lay in a noncoding region of the genome.

Rinn, now an assistant professor of pathology at Harvard Medical School, worked with collaborators to use the chromatin signature to scan a large portion of the genome for more RNAs like this. Their search turned up 1,600 of them, from which they speculate that some 5,000 exist throughout the genome. All of the hits were found in gene deserts, leading to their name: large intervening noncoding RNAs, or lincRNAs. The team looked at 22 different tissue types and "made a pipeline of guilt by association" that tracked which lincRNAs seemed associated with particular protein-coding genes, using that information to infer function. "Now we kind of have a nice map and a nice way of predicting what they're doing," Rinn says.

To that end, while lincRNAs have shown up with implications from stem cell pluripotency to cancer, Rinn says, he suspects they'll wind up sharing a common mechanism in much the way microRNAs do. So far, he says, it seems lincRNAs all "bind chromatin modifying complexes," which could be a common thread for the ones yet to be discovered as well. "They look just like protein coding genes," Rinn says. "The way they're packaged in the DNA is the exact same way [genes are] packaged — which makes us think if these things have the same sort of properties maybe they're just as important."

While the original work was done in mouse, Rinn says studies on lincRNAs have now moved into human. The next step will be to "perform a loss of function experiment for every single one of these," he says. His team will be working with RNAi platforms at the Broad Institute to start with embryonic stem cells, where he posits that lincRNAs are "functioning to bind and guide chromatin complexes." He'll also be keeping a sharp eye out to see if there really is a general mechanism for all lincRNAs.