An RNA Switch for Stem Cells

RNA molecules have long been known for their role in translating genes to proteins inside a cell, but more recently, scientists have found large numbers of RNA molecules that don’t code for proteins but seem to have other cellular roles. Most research in mammals has focused on tiny RNA molecules called microRNAs, but a new study, published this week in Nature, describes the far-reaching effects of much larger and relatively unstudied RNA molecules called lincRNAs (short for large intergenic noncoding RNAs). The study identifies lincRNAs that play a role in the function of embryonic stem cells, and suggests trying to use lincRNAs to manipulate these cells to spawn other cell types.

Mitchell Guttman, first author of the study and a graduate student at MIT and the Broad Institute, says that when the Broad team discovered more than 3,500 unique lincRNAs in the human and mouse genomes in 2009, “the potential was enormous, and we wanted to know what they could be doing.”

To answer that question, the researchers focused on understanding lincRNAs’ role in embryonic stem cells. Using a technique called RNA interference, they systematically shut down the function of each of more than 200 lincRNAs previously identified as playing a role in embryonic stem cells. They then profiled the genes expressed in the cells and studied their functions. They found that most lincRNAs have widespread effects on cells, and that they help control the fate of stem cells. The team identified about two dozen lincRNAs that help maintain the cell’s pluripotency—its ability to beget all other kinds of cells—and a similar number of lincRNAs that repress genes involved in differentiating into other cell types.

Nudging stem cells to differentiate has proved challenging so far, and scientists have been looking for better ways. Guttman says that inhibiting lincRNAs in specific combinations may make it possible to direct stem cells to transform in specific ways. George Daley, a stem-cell biologist at Harvard Medical School and Children’s Hospital Boston, says that further probing the effects of lincRNAs “will help refine our capacity to control and manipulate cells in culture, and this will advance the utility of stem cells for regenerative medicine.”

Tariq Rana, an RNA biologist at Sanford-Burnham Medical Research Institute in La Jolla, California, calls the work “the first comprehensive study defining the functional roles of lincRNAs in embryonic stem cells.” He says it will launch new investigations into how lincRNAs regulate gene expression.

Guttman and colleagues propose that lincRNAs have an important coordinating function in the cell: like sergeants commanding military units, single lincRNAs seem to interact with and control large complexes of proteins. He says that these large RNAs also seem to be put together in a modular way, like molecular Tinkertoys. Learning how they’re put together could allow scientists to design and assemble RNAs to perform very specific tasks—and manipulate cells.