Researchers at Caltech have discovered how an abundant class of RNA genes, called long non-coding RNAs (lncRNAs, pronounced link RNAs) can regulate key genes. By studying an important lncRNA, called Xist, the scientists identified how this RNA gathers a group of proteins and ultimately prevents women from having an extra functional X-chromosome--a condition in female embryos that leads to death in early development. These findings mark the first time that researchers have uncovered the detailed mechanism of action for lncRNA genes. "For years, we thought about genes as just DNA sequences that encode proteins, but those genes only make up about 1 percent of the genome. Mammalian genomes also encode many thousands of lncRNAs," says Assistant Professor of Biology Mitch Guttman, who led the study published online in the April 27 issue of the journal Nature. These lncRNAs such as Xist play a structural role, acting to scaffold--or bring together and organize--the key proteins involved in cellular and molecular processes, such as gene expression and stem cell differentiation.

Guttman, who helped to discover an entire class of lncRNAs as a graduate student at MIT in 2009, says that although most of these genes encoded in our genomes have only recently been appreciated, there are several specific examples of lncRNA genes that have been known for decades. One well-studied example is Xist, which is important for a process called X chromosome inactivation.

All females are born with two X chromosomes in every cell, one inherited from their mother and one from their father. In contrast, males only contain one X chromosome (along with a Y chromosome). However, like males, females only need one copy of each X-chromosome gene--having two copies is an abnormality that will lead to death early during development. The genome skirts these problems by essentially "turning off" one X chromosome in every cell.

Previous research showed that Xist is essential to this process and does this by somehow preventing transcription, the initial step of the expression of genes on the X chromosome. However, because Xist is not a traditional protein-coding gene, until now researchers have had trouble figuring out exactly how Xist stops transcription and shuts down an entire chromosome.

"To start to make sense of what makes lncRNAs special and how they can control all of these different cellular processes, we need to be able to understand the mechanism of how any lncRNA gene can work. Because Xist is such an important molecule and because so much is known about what it does, it seemed like a great system to try to dissect the mechanisms of how it and other lncRNAs work," Guttman says.