An epigenetics gold rush: new controls for gene expression
How rediscovered chemical tags on DNA and RNA are shaking up the field.
22 February 2017
Some big ideas seem to appear out of nowhere, but in 2008 Chuan He deliberately went looking for one. The US National Institutes of Health had just launched grants to support high-risk, high-impact projects, and He, a chemist at the University of Chicago in Illinois, wanted to apply. But he needed a good pitch.
He had been studying a family of proteins that repair damaged DNA, and he began to suspect that these enzymes might also act on RNA. By a stroke of luck, he ran into molecular biologist Tao Pan, who had been investigating specific chemical marks, called methyl groups, that are present on RNAs. The pair worked in the same building at the University of Chicago, and began meeting regularly. From those conversations, their big idea took shape.
At the time, biologists were getting excited about the epigenome — the broad array of chemical marks that decorate DNA and its protein scaffold. These marks act like a chemical notation, telling the cell which genes to express and which to keep silent. As such, the epigenome helps to explain how cells with identical DNA can develop into the multitude of specialized types that make up different tissues. The marks help cells in the heart, for example, maintain their identity and not turn into neurons or fat cells. Misplaced epigenetic marks are often found in cancerous cells.
When He and Pan began working together, most epigenetic research focused on the tags associated with DNA and the histone proteins that it wraps around. But more than 100 different types of chemical mark had been identified on RNA, and nobody knew what they did. Some of the enzymes He was studying could strip off methyl groups, and He and Pan wondered whether one of them might work on RNA. If the marks could be reversed, they might constitute an entirely new way of controlling gene expression. In 2009, they got funding to hunt for reversible marks on RNA and the proteins that erase them.
Nine years later, such research has given birth to an 'ome of its own, the epitranscriptome. He and others have shown that a methyl group attached to adenine, one of the four bases in RNA, has crucial roles in cell differentiation, and may contribute to cancer, obesity and more1, 2. In 2015, He's lab and two other teams uncovered the same chemical mark on adenine bases in DNA (methyl marks had previously been found only on cytosine), suggesting that the epigenome may be even richer than previously imagined3. Research has taken off. “I think we're approaching a golden age of epigenomics and epitranscriptomics,” says Christopher Mason, a geneticist at Weill Cornell Medical College in New York City. “We can actually start to see all these modifications that we knew have been there for decades.”
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