Supplements Restore Gene Function via Methylation

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Science  16 Dec 2005:
Vol. 310, Issue 5755, pp. 1761
DOI: 10.1126/science.310.5755.1761

DURHAM, NORTH CAROLINA— Geneticists, molecular biologists, and epidemiologists discussed epigenetics from 2 to 4 November at the Environmental Genomics, Imprinting, and Disease Susceptibility conference.

It has long been known that pregnant women who consume insufficient folic acid, a B vitamin, run an increased risk of having babies with spina bifida or similar neural tube defects. Yet biologists are still teasing out exactly what this vitamin does for the developing fetus. At the meeting, Robert Waterland, an epigeneticist at Baylor College of Medicine in Houston, Texas, presented evidence from mice that methylation of DNA—a chemical modification that can shut down genes—can be key.

Folic acid does restore gene function in mutant mice that have improper DNA methylation patterns, the researcher reported. However, Waterland has also found that the supplement-induced changes in DNA methylation might not be all that predictable—they appear to occur at different points in time during embryonic development and to affect only specific tissues, he reported.

These mouse results may have implications for supplement use in both pregnant women and the public at large. “People are taking massive quantities of vitamins, and we don't have any idea what these potential methyl donors are doing,” says Adele Murrell, a geneticist at the University of Cambridge, U.K.

Straighten out.

Methylation stimulated by supplements helps unkink the tails of mutant mice.


Waterland first observed the embryonic impact of folic acid and other methyl donors 2 years ago, while working with Randy Jirtle at Duke University in Durham, North Carolina. At that time, he examined a strain of off-colored mice that has a defect in a pigment gene called agouti—the gene is defective because a mobile bit of DNA called a transposable element had inserted itself in some of the nearby DNA that regulates the gene's expression. The transposable element short-circuits methylation of this regulatory region, causing the gene to be overactive. As a result, yellow or mottled coats are common in these animals. But litters born to dams fed supplements of folic acid, a rich source of methyl groups, were primarily the typical brown. Waterland and his colleagues subsequently found that the supplements caused an increase in the density of methyl groups on and around the agouti gene, overriding the transposable element's effects.

Waterland has since investigated a gene that may be more relevant to human disease. The axin gene helps set up the dorsal-ventral axis in embryos and also requires methylation to work properly. Many mice with an axin disrupted by a transposable element embedded in it typically develop mild to tightly angled kinks in their tails. Again, methyl donors can come to the rescue. Waterland reported that receiving folic acid supplements during pregnancy reduced by half kinking in the pups' tails. Taken together, “Waterland's data are the most convincing positive finding with respect to whether diet has any effect on the methylation patterns and expression of a particular [gene],” says Carmen Sapienza, a geneticist at Temple University in Philadelphia, Pennsylvania.

Folic acid supplementation altered the methylation of the two genes in different ways, however, illustrating the complexity of the phenomenon. In the agouti mice, the supplements increased methylation of the gene in a variety of tissues, and the change was most pronounced early in pregnancy. But in the case of the axin mice, that gene's methylation remained low early in pregnancy and only increased later on, as the tail formed, Waterland reported. Moreover, the increase occurred only in the tissue giving rise to the tail. These two observations suggest to him that DNA methylation produced by vitamin supplementation can be tissue-specific and, depending on the gene involved, can occur at different times over the course of a pregnancy.

Waterland's research may one day lead to more sophisticated timing of when to give vitamin supplements to pregnant women or anyone else. “If we can understand critical windows and when methylation is beneficial,” says Patrick Stover, a nutritional biochemist at Cornell University, “that would totally change the concept of how we set dietary requirements during pregnancy and how we think about preventive medicine.”

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