Modifying Messenger RNA

For decades researchers have known that every strand of messenger RNA in a cell has five or six adenosine bases that are methylated, but nobody could figure out why this ubiquitous decoration exists.

Now a team of scientists led by Chuan He at the University of Chicago have found an enzyme that can remove the methyl group from mRNA. This first report that RNA bases can be reversibly modified suggests that RNA methylation may have a role in regulating gene expression, reminiscent of the way methylation of DNA silences genes (Nat. Chem. Biol., DOI: 10.1038/nchembio.687).

Furthermore, the researchers found the enzyme that removes the methyl groups to be FTO, a protein that is linked to obesity and diabetes but whose cellular role was not clear. This finding suggests that RNA methylation helps regulate multiple biological processes.

“This is an exciting result,” comments Roger D. Cox, an obesity researcher at the U.K.’s Medical Research Council’s Harwell campus. Back in 2007, three independent, large-scale genome studies found that the FTO gene had links to severe obesity in both adults and children and led to obesity-related diabetes (Science, DOI: 10.1126/science.1141634 and 10.1126/science.1142382; Nat. Gen., DOI: 10.1038/ng2048).

But “we don’t know exactly what the FTO protein does in a cell,” Cox says. “There’s a gap between the obese phenotype and the molecular mechanism” behind it. “This new research gives us a toehold to find out exactly what FTO’s doing in a cell that leads to obesity,” starting with the demethylation of mRNA, he adds.

Mark Helm, who studies RNA at Johannes Gutenberg University, in Mainz, Germany, is more enthused by the larger implications stemming from the news that mRNA may be transiently methylated.

He says that about 120 modifications exist on RNA’s four bases—adenine, cytosine, guanine, and uracil. Although some of these are fancy installations of exotic sugars and other ring structures, one of the most common is the mundane methylation of adenine to create a base called m⁶A.

The discovery that mRNA can be demethylated suggests that the m⁶A modification might have a role as a toggle switch to regulate gene expression at the mRNA level, Helm says.

When scientists realized that enzymes could pop methyl groups on and off cytosine bases in DNA and that this reversible modification silenced or activated gene expression, the discovery spawned a new field called epigenetics. “This paper will spawn a lot of new research,” Helm adds.

However, if reversible methylation of mRNA adenine bases is indeed a new way to control gene expression, then there must be more than just the FTO enzyme that can trigger the reaction—it’s got to be more universal, Helm says.

Chicago’s He agrees, noting that his team has found evidence that other enzymes can also demethylate mRNA, providing further confirmation that methyl groups on RNA might help control gene expression.