Science News - December 17, 2011

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Seeing patterns Researchers recently identified 30 lincRNAs that appear to act as barriers preventing an embryonic stem cell from turning into various tissue types. Blue boxes indicate where the knockdown of a lincRNA led to genetic activity patterns characteristic of differentiation.

Just how lincRNAs choose which genes to turn on and off isn’t yet known. But Pier Paolo Pandolfi, a geneticist at Beth Israel Deaconess and Harvard Medical School, suspects that the linc RNAs are whispering to each other and to other RNAs, keeping tabs on all a cell’s goingson. Pandolfi laid out his hypoth esis for how this chatter might help control protein production and other processes in the Aug. 5 Cell.

Proteincoding messenger RNAs are often prevented from making their instructions into proteins by tiny snip pets of RNA called microRNAs. The microRNAs glom on to certain messenger RNAs like paparazzi crowding a celebrity.

If lincRNAs and messenger RNAs share a string of chemical letters that interest the microRNAs, the lincRNAs can serve as a decoy, distracting micro RNAs so messenger RNAs can get their jobs done. As long as two molecules both have the signatures that the microRNAs seek, the little RNAs will clamor around both messages with equal fervor.

Last year, Pandolfi’s group found that the RNA copied from a pseudo gene (a defunct copy of a gene that no longer makes proteins) can attract microRNAs away from the messen ger RNA copied from a real gene called PTEN, which is important in pro tecting against cancer (SN: 7/17/10, p. 14). That finding led to the suggestion that, by acting as decoys, RNAs could regulate protein production or other processes within a cell. Pandolfi calls this idea the ceRNA hypothesis (for “compet ing endogenous RNA”).

A growing body of evidence suggests

that Pandolfi’s hypothesis is more than just a clever idea. Researchers at Columbia University performed a com puterized search of the human genome and found 7,000 genes whose messenger RNA copies could act as microRNA decoys in 248,000 interactions, a result reported in the Oct. 14 Cell.

The Columbia team and Pandolfi’s team independently found that tweak ing levels of a few messenger RNAs that distract microRNAs from PTEN messen ger RNA can lead to prostate cancer or a type of brain tumor called glioblastoma. Just messing with levels of a messenger RNA from another gene known as ZEB2 throws off PTEN protein levels and can lead to melanoma in mice, Pandolfi’s group reported in another paper in the Oct. 14 Cell.

Some lincRNAs also appear to contain microRNA magnets. Researchers from Italy report in the same issue of Cell that they have found an RNA called linc-MD1 that is important in muscle develop ment. The lincRNA sponges two micro RNAs away from the messenger RNA of two genes, allowing more muscle building proteins to be made from those genes. Cells taken from people with Duchenne muscular dystrophy have lower levels of linc-MD1 than normal muscle cells do. Without linc-MD1 to draw them away, the microRNAs pile on to the messenger RNAs and prevent the muscle proteins from being made.

With so many interconnected parts in the system, researchers need to think carefully about the consequences of tweaking levels of any RNA within a cell, Pandolfi says.

If any decoy isn’t made, potentially hundreds of conversation partners could be affected, with amounts of proteins they each produce being altered by 10 to 30 percent.

“People say, ‘that’s ridiculous. That’s nothing,’ ” Pandolfi says. But if 200 or more conversation partners are each per turbed by 10 percent, “that’s devastating.” Losing one noncoding RNA may be disastrous for a cell, but for want of non coding RNAs whole species may never have evolved, argues Queensland’s Mattick. He and others say the real function of lincRNAs is to give evolu tion a sort of molecular clay from which to mold new designs.

New proteins rarely appear, leav ing evolution a limited set of building materials to work with, Mattick says. But new lincRNAs pop up all the time; some of them appear in only one species. Given the molecules’ jobs as directors and overseers, evolution may use them to make design variations on the fly.

Humans have several lincRNAs that are found in no other species. Many of those RNAs are made in the brain, leading scientists to speculate that the molecules may be at least partially responsible for that important organ’s evolution.

If Mattick is right, making a human from the same building materials used to create roundworms and fruit flies doesn’t pose such a puzzle. It does, however, mean finding the right contractors. s