February 1, 2011

Prenatal Nutrition Writes Large On Human Epigenome

Think of your genome as a dynamic outdoor sculpture. Its shape is, of course, influenced by its structural underpinnings "“ the double helix containing phosphate and two chains of nucleotides attached to a sugar called deoxyribose. These chains wind around each other, linked by hydrogen bonds between the specific bases "“ adenine to thymine and cytosine to guanine.

But forces outside your sculpture also act on it. If it were really outside, the forces would be wind, rain, sunlight and the depredations of humans and animals. Your genomic sculpture, however, is affected by forces inside the cell. There, chemical reactions attach molecules that turn genes on and off or affect the level of activity or how the genetic code is translated into the workhorse proteins of the cell. This is called epigenetics. These epigenetic changes can affect people's health and risk of disease for the rest of their lives.

Many influences can affect epigenetics, but one of the most potent appears to be nutrition before birth.

Study in rural Gambia

That is true in rural Gambia where seasonal variation in maternal nutrition causes infants born during the food-scarce rainy season to weigh 200 to 300 grams (7 to 10.5 ounces) less than babies born at other times of the year, said researchers from Baylor College of Medicine and the London School of Hygiene and Tropical Medicine, who reported on their findings in a recent issue of the open access journal PLoS Genetics.

Dr. Robert Waterland, an assistant professor of pediatrics in the USDA/ARS Children's Nutrition Research Center at BCM and Texas Children's Hospital, and his colleagues found that this seasonal variation permanently changes a child's epigenome, which controls how genes are expressed.

In particular, said Waterland, the seasonal effect occurs in specific parts of the genome that are briefly unstable during an embryo's development. During this period "“ just before fetal development, when early cells differentiate into the various tissues "“ the potential for genes in these regions to be expressed is switched on or off by chemical marks on the DNA.

Metastable epialleles

"Once that is set, it is maintained for life," said Waterland, who is also a member of the department of molecular & human genetics at BCM. During fetal development, the original chemical marks at these regions, called metastable epialleles, are propagated throughout the body.

Metastable epialleles have long been known to exist in mice. That is why mice with the same genetic blueprint can have different coat colors. In previous work, Waterland showed that what their mothers eat during pregnancy can permanently turn off or on genes in these areas of the genome in the offspring, changing their coat color for life. The changes were not in their genes but in how those genes functioned.

Genome-scale screening

Waterland collaborated with Dr. Andrew M. Prentice of the London School of Hygiene and Tropical Medicine, who has been working in Gambia for decades. In their study, they used a special human genome-scale screening approach to look for variations in DNA methylation "“ an epigenetic event in which adding a certain molecule to a gene can turn it off. They looked for these in both blood and hair follicles of test subjects and identified areas of the genome where variation among individuals is similar in both tissues.

To confirm that these epigenetic differences are not caused by differences in the genes themselves, they also examined the genomes of 23 pairs of identical (monozygotic) twins, who have the same genetic blueprint. Even genetically identical twins often had different methylation (the addition of a methyl molecule) at these special regions, indicating that the chemical marking occurred randomly during early development.

Blood tests of Gambian chidlren

To test whether this random process is influenced by nutrition, they then evaluated these sites in blood drawn from Gambian children, comparing those conceived during the rainy season to those conceived in the dry season over four different years. At all five proposed metastable epiallele sites, they found more methylation in the children conceived during the rainy season. The season of a child's conception was the only variable that predicted the methylation or epigenetic change they found.

The next step is to find out what this means to the children's health in later life.

"The biggest contribution of this research," said Waterland, "is that we have identified an approach for finding human metastable epialleles by simultaneously screening multiple tissues for methylation differences among individuals."

"The Gambian findings were icing on the cake," he said. "Amazingly, these samples were collected from children around 9 years old, who have lived through several seasonal cycles but were still left with this epigenetic mark throughout their bodies that was linked only to the season of their conception. That gives a mechanistic insight to explain how early nutritional exposure in the human can lead to long term changes in health status."

Others who took part in this work include Richard Kellermayer, Eleonora Laritsky, R. Alan Harris, Wenjuan Zhang, Maria S. Torskaya, Lanlan Shen and Mark J. Manary of BCM; Pura Rayco-Solon of the London School of Hygiene and Tropical Medicine, Michael Travisano of the University of Minnesota and Jiexin Zhang of The University of Texas MD Anderson Cancer Center.

Funding for this research came from the March of Dimes Foundation, the NIH, the U.S. Department of Agriculture, and the Curtis and Doris K. Hankamer Foundation to R.A.W. The MRC International Nutrition Group is funded by the UK Medical Research Council.


On the Net: