Sunday, January 18, 2009

Epigenetics reveals unexpected, and some identical, results

Epigenetics reveals unexpected, and some identical, results

One study finds a unique signature in the genome; another a specific similarity between identical twins in DNA’s chemical alternationBy Tina Hesman Saey Web edition : Sunday, January 18th, 2009 Text Size Tattoos on the skin can say a lot about person. On a deeper level, chemical tattoos on a person’s DNA are just as distinctive and individual — and say far more about a person’s life history.

A pair of reports published online January 18 in Nature Genetics show just how important one type of DNA tattoo, called methylation, can be. Researchers at Johns Hopkins University report the unexpected finding that most DNA methylation — a chemical alteration that turns off genes — occurs most often near, but not precisely within, the DNA regions on which scientists have typically focused their studies. The other report, from researchers at the Universityof Toronto and collaborators, suggests that identical twins owe their similarity not only to having the same genetic make-up, but also to certain methylation patterns established in the fertilized egg.

Methylation is just one of many epigenetic signals — chemical changes to DNA and its associated proteins — that modify gene activity without altering the genetic information in the genes. Methylation and other epigenetic signals help guide stem cells as they develop into other type of cells. Scientists have long suspected that mishandling methylation and other epigenetic flags could lead to cancer.

The Johns Hopkins group has now shown that DNA methylation is more common at what they call “CpG island shores” instead of at the CpG islands that most researchers have been studying. CpG islands are short stretches of DNA rich in the bases cytosine and guanine, also known as C and G in the genetic alphabet. (Adenine (A) and thymine (T) are the other DNA bases.) CpG islands are located near the start site of genes and help control a gene’s activity. Planting a chemical flag called a methyl group on an island declares the gene off-limits, blocking activity.

Researchers have also thought of CpG island methylation as a type of long-term memory, preserving environmental effects on genes long after those cues have disappeared, says Rolf Ohlsson, a geneticist at the Karolinska Institute in Stockholm, Sweden.

Scientists have long suspected that differences in epigenetic marks shaped by environmental cues could account for why identical twins don’t look, behave or get sick exactly alike despite having identical genetic make-ups. But no one had mapped out all the places, if any, where epigenetic marks differ between twins.

Now researchers led by Arturas Petronis at the University of Toronto have explored all of the CpG islands dotting the genome to see which sport methylation flags. The team compared the methylation patterns of co-twins from monozygotic pairs — twins created when a single embryo splits. Although the twins had identical DNA, their methylation of CpG islands varied. But the methylation patterns in monozygotic twins were more similar than for dizygotic twins, fraternal twins who develop from two separate eggs. And the group found that the amount of variation between monozygotic twins correlates with the time the embryo split. Twins from an early-splitting embryo have more similar methylation patterns than twins from a later split.

Epigenetic patterns established in the early embryo are carried throughout life with some differences introduced by the environment and others by random chance and error in replicating the patterns as the person develops. DNA is reproduced with high fidelity — mistakes happen in about one in a million bases — but the process of reproducing epigenetic patterns in dividing cells is rather more error-prone, with one in a thousand epigenetic marks going awry.

Petronis thinks the similarity between monozygotic twins results not from shared DNA sequences but from having come from the same embryo. “We don’t see any reason to think that the DNA sequence makes up the epigenetic profile,” Petronis says.

But swimming away from CpG islands may give researchers an entirely different perspective on the problem.

Andrew Feinberg, director of the Epigenetics Center at Johns Hopkins University in Baltimore, and his colleagues embarked on a genome-wide tour to chart DNA methylation in different human tissues. The researchers had expected that each tissue would have a characteristic pattern of methylation, indicating which genes were turned off and which are turned on to build a liver, spleen, brain or other type of tissue. Often researchers examine methylation only at CpG islands, but Feinberg says that most islands are free of methylation in most tissues.

“We were always a bit skeptical of this island thing,” he says. So the team used a method that could reveal every place in the genome where a methylation flag was staked.

The researchers did find characteristic patterns in each type of tissue, but not where they thought they would. Methylation flagged the DNA in liver, spleen and brain at thousands of places near, but not in, CpG islands. Feinberg and his colleagues are calling the close-by stretches of methylated DNA “CpG island shores.”

“This is a discovery that is totally unexpected,” says Ohlsson. Feinberg and his colleagues have found “a signature of the genome that we weren’t aware of before.”

DNA in mouse tissues also has “shore” methylation patterns similar to those in corresponding human tissues. About 51 percent of the shores methylated in mouse tissues were also methylated in human tissues, indicating that DNA methylation of CpG island shores is an ancient, and important, method of controlling genes, Feinberg says.

When looking at colon cancer tumors, Feinberg and colleagues found that cancer cells showed methylation patterns more eroded at the shores than in healthy colon cells. Feinberg thinks that a breakdown in the patterns may cause colon stem cells to develop inappropriately, leading to cancer.

Unpublished research conducted by Dag Undlien of the University of Oslo, while on sabbatical in Feinberg’s lab, indicates that monozygotic twins share more shore methylation patterns than dizygotic twins do, and are even more similar than Petronis’ research suggests, Feinberg says.

Feinberg thinks evidence from his lab, though preliminary, indicates that DNA sequence does help determine epigenetic patterns. He calls Petronis’ report, “a terribly interesting paper,” but adds, “I think there may be a stronger genetic contribution than is suggested by his data.”

Regardless of who is correct about the degree of similarity between twins, Ohlsson says that Feinberg’s discovery of CpG island shores will force scientists “to refocus our efforts to figure out what DNA methylation is doing.”

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