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You can hit ‘undo’

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Once a chisel hits marble, there’s no second chance for a sculptor. Many researchers thought that once a methyl group was attached to DNA, the modification was also set in stone. Carbon–to–carbon bonds between the methyl group (one carbon and three hydrogens) and the DNA base are too strong to sever, the reasoning goes. Only five years ago, Michael Meaney, a behavioral geneticist at McGillUniversity in Montreal, Canada, submitted a manuscript to a scientific journal detailing experiments showing that some genes can be demethylated — the methyl group can be plucked off the DNA base cytosine to which it is attached. The editor of the journal rejected the paper, saying that demethylation “just doesn’t happen,” Meaney says.

But recent evidence from Meaney’s lab and others shows that DNA methylation is less like sculpting in marble and more like working with clay.

It’s true that DNA methylation is the most enduring of epigenetic modifications, says Frances Champagne, a neuroscientist at ColumbiaUniversity.

“It can be very stable, but it is just a chemical bond,” Champagne says. And chemical bonds are made to be broken.

J. David Sweatt’s group at the University of Alabama at Birmingham has been investigating methylation of the gene for BDNF. The researchers found that demethylation happens rapidly under certain conditions, such as when people experience stress.

“It seems solid in my mind that experience can trigger genes’ demethylation,” Sweatt told colleagues gathered in Houston in March for a symposium on epigenetics and behavior.

But even scientists who agree that demethylation is real don’t know exactly how it happens.

A group of European scientists presented evidence in the March 6 Nature that demethylation is carried out by a cellular system that tracks down and repairs mutations.

Cytosines with methyl groups stuck to them look very much like the DNA base thymine, and sometimes methylated C’s get converted to T’s. That creates a mismatch with the G on the opposite DNA strand. Cellular machinery scans the DNA for such mismatches, snips out the offending T and replaces it with a new C — one without a methyl group attached.

But the excision and repair system is probably only one way to pick methyl groups off DNA, Meaney says. He and others think the same enzymes that tag DNA with methyl groups also remove the modifications.

“The enzyme may work in both directions,” Meaney said at the March meeting, “and this is not odd for an enzyme to be able to work in that way.”

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.

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