One lab mines for microRNAs

By Melissa Lee Phillips

On a wall in Thomas Tuschl's Rockefeller University lab hangs a huge painting created by a street artist. The large, bright figures wearing white lab coats and nametags are members of the Tuschl lab, circa 2004. In the background of the painting, drawings on a green chalkboard illustrate a simplified rendering of the RNA interference pathway. In a 15th floor lab overlooking the East River between Manhattan and Brooklyn, the 2007 version of this group (about a dozen researchers) continues to decipher the mysteries of microRNAs (miRNAs).

Today, scientists have worked out many general properties of miRNAs in the plants, animals, and viruses that encode them. Double-stranded RNA molecules are cleaved by enzymes, including Drosha and Dicer, into mature miRNAs of about 22 nucleotides each....

mRNA Target predictions "do a really good job, but they still need validation," according to Klaus Rajewsky of Harvard Medical School.

Over the last few years, researchers have identified hundreds of miRNAs that control both general and tissue-specific functions. Last April, three groups revealed the world's first miRNA knockout mice. While mRNA target prediction is still a tricky business, many groups are working on computer algorithms that predict possible mRNA targets based on sequence complementarity with miRNAs. These predictions "do a really good job, but they still need validation," according to Klaus Rajewsky of Harvard Medical School. For most miRNAs, it's not clear if they actually bind to their potential mRNA targets in vivo, he says.

Tuschl's group recently compiled cloning and sequencing data - from "every type of cell or tissue that we could get a hold of," he says - into an extensive survey of mammalian miRNA expression (Cell, 129:1401-14, 2007). Tuschl's analysis showed that many miRNAs are expressed in a variety of cell types and tissues, but "from the few hundred microRNAs that we have, there's a surprising number of them that have very interesting specificity," he says.

John Pena, an MD/PhD student in Tuschl's lab, is exploring both specific and non-specific miRNAs in the mammalian brain. He uses a stereotactic instrument (something like what surgeons use to ensure accurate positioning during brain surgery) to inject molecules that inhibit miRNA activity in the mouse brain. Because the instrument can zero in on tiny locations in the brain, Pena can study miRNA activity in individual neurons. Eventually, "we're going to make a three-dimensional map of all the microRNAs in the brain," he says.

The researchers are collaborating with scientists at the Allen Institute for Brain Science in Seattle, to match miRNA expression with mRNA expression in the same areas of the brain. They hope this will help reveal the mRNAs that are targeted by nervous system miRNAs. These studies are still at the very beginning, Tuschl says, and not just in his lab, but everywhere. At the moment, they're simply depriving different brain areas of certain miRNAs and watching what happens. "It's sort of random," he says.

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