Genetic discovery will revolutionize understanding of gene expression

Over the past decade, research in the field of epigenetics has revealed that chemically modified bases are abundant components of the human genome and has forced us to abandon the notion we've had since high school genetics that DNA consists of only four bases. Now, researchers at Weill Cornell Medical College have made a discovery that once again forces us to rewrite our textbooks. This time, however, the findings pertain to RNA, which like DNA carries information about our genes and how they are expressed. The researchers have identified a novel base modification in RNA which they say will revolutionize our understanding of gene expression. Their report, published in the journal Cell, shows that messenger RNA (mRNA), long thought to be a simple blueprint for protein production, is often chemically modified by addition of a methyl group to one of its bases, adenine. Although mRNA was thought to contain only four nucleobases, their discovery shows that a fifth base, N6-methyladenosine (m6A), pervades the transcriptome. The researchers found that up to 20 percent of human mRNA is routinely methylated. Over 5,000 different mRNA molecules contain m6A, which means that this modification is likely to have widespread effects on how genes are expressed. "This finding rewrites fundamental concepts of the composition of mRNA because, for 50 years, no one thought mRNA contained internal modifications that control function," says the study's senior investigator, Dr. Samie R. Jaffrey, an associate professor of pharmacology at Weill Cornell Medical College. "We know that DNA and proteins are routinely modified by chemical switches that have profound effects on their function in both health and disease. But biologists believed mRNA was simply an intermediate between DNA and protein," he says. "Now we know mRNA is much more complex, and defects in RNA methylation can lead to disease." Indeed, as part of the study, the researchers demonstrated that the obesity risk gene, FTO (fat mass and obesity-associated), encodes an enzyme capable of reversing this modification, converting m6A residues in mRNA back to regular adenosine. Humans with FTO mutations have an overactive FTO enzyme, which results in low levels of m6A and causes abnormalities in food intake and metabolism that lead to obesity. The researchers uncovered links between m6A and other diseases as well. "We found that m6A is present in many mRNAs encoded by genes linked to human diseases, including cancer as well as several brain disorders, such as autism, Alzheimer's disease, and schizophrenia," says the study's lead investigator, Dr. Kate Meyer, a postdoctoral researcher in Dr. Jaffrey's laboratory.