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Nuture Takes The Spotlight Decoding the environment's role in development and disease

By Christen Brownlee, Science News

25 April 2006: Identical twin sisters Elizabeth and Eleanor (not their real names) say that when they entered the world on November 19, 1939—Elizabeth first, then Eleanor 8 minutes later—their mother was rather shocked. She'd been expecting just one baby, not two. But that day, she made a vow: The girls would always be treated the same, so that there would be no competition between them.

Press Photo

POSTER CHILDREN. Illustrating how epigenetics can control physical traits, the slimmer and browner of these mice, carrying a gene called agouti, were born to mothers that ate more DNA-methylating foods. Jirtle/Environmental Health Perspectives

Their mother was true to her word. As children, Elizabeth and Eleanor wore the same outfits in the same colors, shared school classes, and had the same group of friends. "We were treated like a unit—more like one person instead of two separate individuals," says Elizabeth.

Although they moved to different locales more than 43 years ago, the women still resemble each other and have similar interests. However, 7 years ago, a critical difference emerged. A lump in Eleanor's breast turned out to be cancer, but Elizabeth remains cancerfree.

When Eleanor thinks about why she, and not her sister, was the unlucky one, she doesn't focus on genetics. Like all identical twins, she and Elizabeth inherited the same genes. "Genetics has a big influence on who a child is—there's no mistake about that. But you can't rule out nurture, the contribution of the environment," she says.

Mounting scientific evidence suggests that Eleanor's view is on target. Six years after researchers from around the world finished a first read of the human genome, it's becoming increasingly clear that genes don't tell the whole story of a person's looks, personality, and health.

New studies suggest that what a person eats, what chemicals he or she is exposed to, and other features of a person's environment put in place chemical modifications to the chromosomes, thereby changing how genes are ultimately expressed. This emerging area of study, known as epigenetics, is examining how such modifications affect development and play a role in diseases ranging from cancer to schizophrenia.

Mouse of a different color

As early as the 1940s, researchers who couldn't explain some of an organism's attributes by straightforward Mendelian genetics started calling these aberrant traits epigenetic, says Randy Jirtle, a researcher who studies gene control at Duke University in Durham, N.C. "'Epigenetics' literally means 'above the genome,'" he explains.

Scientists eventually learned how apt the name was. Inspecting the double helix turned up hundreds of thousands of what scientists colloquially call "marks"—places where DNA is tagged with carbon and hydrogen bundles known as methyl groups. Enzymes attach methyl groups only at points on the genome where two DNA components—cytosine and guanine—meet. These components often cluster near the beginning of a gene, where proteins attach to turn on genes. If a methyl group blocks a protein from binding, the gene typically stays switched off.

In recent years, scientists have learned that methylation isn't the only mark that changes whether genes are expressed. Various chemical groups clip on to histones, the spools around which DNA wraps when it condenses into chromosomes. These groups can affect how tightly DNA is packed. Although histone modification is not as well studied as methylation, researchers have shown that genes on loosely packed DNA are more likely to be expressed than are those on DNA that's tightly wound.

Most of these epigenetic marks are set by cells long before an animal's birth, says Jirtle. Each type of cell, from liver to skin to muscle, carries a distinct pattern of methylation and histone modifications that, for the long term, switch genes on or off in the pattern necessary for the cell to do its job.

However, Jirtle adds, not all of these marks are set in stone. Outside factors during development can change which DNA segments are epigenetically modified, setting the stage for traits that linger into adulthood.

Three years ago, Jirtle and his Duke colleague Robert Waterland illustrated how easily epigenetically controlled traits can be changed. The researchers were working with a strain of mice that carry a gene called agouti. Mice with this gene have brindled fur that ranges in color from yellow to brown. When the researchers supplemented pregnant animals' food with vitamin B12, folic acid, choline, and betaine—a nutrient from sugar beets—the offspring typically grow brown coats. Those mothers that hadn't received the supplements gave birth to babies that grew yellow fur.

Jirtle and his colleagues recently repeated the experiment using supplements of genistein, a nutrient derived from soybeans. The team used amounts, scaled down for the mouse's size, in a typical human diet in Asia.

The researchers report in the April Environmental Health Perspectives that giving pregnant mouse mothers genistein not only shifted their offsprings' coat colors toward brown but also decreased the babies' chances of developing various diseases, such as obesity, diabetes, and cancer.

Jirtle says that these profound effects occur because the nutrients influence methylation, often by directly contributing methyl groups that can migrate onto DNA and shut off genes. Although the DNA sequence within the agouti gene was the same in all the offspring, methylation in the animals that grew brown coats had shut off that gene as well as a cascade of others important for diseases.

Some scientists are showing that factors other than foods, drugs, and environmental chemicals can also change a developing organism's gene expression. For example, the attention that a young animal receives from its mother can have long-lasting effects on genes that affect its behavior in adulthood, says Moshe Szyf of McGill University in Montreal.

Researchers had long known that rat pups that don't receive as much licking and grooming—perhaps a rat mother's brand of affection—grow up to have more-exaggerated stress behavior than better-cared-for pups do. In 2004, Szyf and his colleagues showed that rats that aren't adequately licked and groomed as babies end up with a methyl group on a gene that makes the glucocorticoid receptor, a brain cell—surface protein essential for the stress response. Less-well-tended rats methylate that gene, says Szyf.

He and his colleagues published a paper in the Feb. 28 Proceedings of the National Academy of Sciences showing that the effects of maternal care, good or bad, needn't be permanent. Administering drugs that put on or knock off methyl groups changed the glucocorticoid-receptor gene's methylation status in adulthood and, therefore, how much stress the animals experienced.

Szyf and his colleagues are now attempting to determine whether a human mother's care for her baby has a similar effect. However, he points out that the study in rats illustrates one potential benefit of epigenetic modifications. During evolution, a pivotal gene typically changes only slowly, but the environment around an organism can change quickly, Szyf explains.

Thus, if a mother has cause to be stressed and is too preoccupied to groom her pups, her offspring had better prepare themselves for stressful lives. "Epigenetics gears us toward the world we'll be finding ourselves in," Szyf says.

Making a mark These epigenetic adjustments don't stop during youth-marks in the genome can shift throughout adulthood and into old age. For example, Manel Esteller of the Spanish National Cancer Center in Madrid and his colleagues reported in the July 26, 2005 Proceedings of the National Academy of Sciences that identical twins who start out with near-identical methylation patterns grow apart epigenetically as they age (SN: 7/9/05, p. 19: http://www.sciencenews.org/articles/20050709/fob1.asp). The researchers found that these differences were magnified in twins that spent the majority of their lives apart.

"We believe these different epigenetic patterns in twins depend many times on the environment," says Esteller, "whether it's exposure to different chemical agents, diets, smoke, or whether people live in a big city or the countryside."

Researchers are still trying to figure out whether an organism has control over the placement of these epigenetic marks.

Although many of these marks could have a positive effect or no effect at all, explains Esteller, numerous studies have suggested that some epigenetic changes have negative effects that increase the likelihood of diseases, including cancer. For example, several studies of cells sampled from cancer patients' tumors have found that tumor-suppressor genes that normally protect a cell from developing cancer are often silenced by epigenetic modifications.

Studying epigenetic modifications and the environmental effects that lead to them could provide information on why people get cancer in the first place, says Andrew Feinberg of Johns Hopkins University in Baltimore. He and his colleagues study a phenomenon called imprinting, in which gene copies take on epigenetic marks that keep them on or off, depending on which parent each copy was inherited from. One copy of a particular imprinted gene, which makes a protein called insulinlike growth factor 2 (IGF2), is normally turned off when inherited from an animal's mother. The copy inherited from an animal's father generally stays on.

In the March 25, 2005 Science, Feinberg's team showed that mice that lose epigenetic control over the maternally inherited copy of the IGF2 gene, and so turn it on, have more than double the risk of getting colon cancer when they later get a cancer-causing genetic mutation. "It looks like it's important for this cancer to have a double dose of IGF2 expression," says Feinberg.

Loss of imprinting and other epigenetic changes could play a role in numerous other diseases, including those that affect mental health. For example, Arturas Petronis of the University of Toronto and his colleagues are analyzing methylation patterns in postmortem brain tissue from autopsies of people who had schizophrenia or bipolar disorder and from people who had good mental health. His team is hoping to spot some critical differences in gene regulation.

Petronis admits that separating the tangled web of cause and effect in mental diseases is a difficult task. Methylation patterns might have contributed to a person's disease, but they might also have been influenced by the numerous psychotropic medications that psychiatric patients often take. Nevertheless, Petronis says, the work is gradually racking up data that could point out genes misregulated in these diseases.

Nurturing patients

One vital feature of epigenetic modifications is that they're faithfully passed down as a cell divides. For example, each cancer cell in a spreading tumor inherits the same epigenetic mishaps as did the cell that originally spurred the disease. However, these marks need not spell out a patient's death sentence. Several pharmaceutical companies are now focusing on creating new drugs that attack the enzymes that chemically modify chromosomes.

A handful of these drugs is already on the market, but it's not clear how they work, says cancer researcher Jean-Pierre Issa of the M.D. Anderson Cancer Center in Houston. However, he notes, researchers suspect that shutting down these enzymes leaves dividing cells without the resources to pass on their epigenetic marks. Therefore, more cells in each new generation are missing the marks that propagated their parent cell's disease.

Regardless of the mechanism, the important thing is that the drugs do seem to fight disease, notes Issa. "The epigenetic approach is working," he says.

In the April 15 Cancer, Issa and his colleagues published the results of a trial of a demethylating drug called decitabine. In 170 patients with a type of blood cancer, about 9 percent of the group was in complete remission after 6 weeks of treatment with the drug, compared with none of the patients who received typical supportive care. About a third of the drug-treated patients had significant improvements in their disease symptoms and progression.

Issa notes that decitabine and other drugs that target gene methylation might work even better when administered with some traditional chemotherapy medications. His team plans on testing that possibility.

While cancer is the primary target of epigenetic therapies for now, some companies are branching out. For example, Montreal-based MethylGene is working on drugs to treat problems ranging from diabetes to neurodegenerative diseases to fungal infections.

Right now, drugs aimed at altering epigenetic marks hit in a random way. They knock off methyl groups that could have positive effects as well as groups that could have harmful ones. For researchers to target treatments to the specific marks that influence a disease, they'd need a map of marks. That's one reason that many researchers, including Peter Jones of the University of Southern California in Los Angeles, are pushing for a human epigenome project.

Similar to the landmark Human Genome Project, the human epigenome project would scan the chromosomes of volunteers to look for similarities and differences in epigenetic patterns. But, notes Jones, comparing epigenomes will be a far more monumental task than mapping genes.

"There are different epigenomes in every tissue—even in every person," says Jones. Challenging decisions confront researchers designing such a project. How many of the body's tissues will they scan? Will they include people of different ages and ethnicities? How will smoking and other lifestyle factors figure in? And how will they handle the enormous amount of information the project will generate?

Someday, notes Jirtle, scientists may paint a complete picture of how nature and nurture work together. But for now, he agrees with identical twin Eleanor's view. "Both nature and nurture are important, and both are intertwined," he says.

"But what's bigger is epigenetics, in terms of bulk," he adds. "Genomics might be the tip of the iceberg, but I truly believe that epigenetics is the base."

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