Epigenetics: from islands to the shores: tissue-specific DNA tagging found in unexpected regions.

By | February 5, 2014

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Tattoos on the skin can say a lot about a 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 DNA methylation–a chemical alteration that turns off

genes–occurs most often near, but not within, the DNA regions

scientists have typically studied. The other report, from researchers at

the University of Toronto and collaborators, suggests that identical

twins owe their similarities not only to having the same genetic makeup,

but also to certain methylation patterns established in the fertilized

egg.

Methylation is one of many epigenetic signals–chemical changes to

DNA and its associated proteins–that modify gene activity without

altering the genetic information itself. Methylation and other

epigenetic signals help guide stem cells as they develop into other

types of cells. Mistakes in methylation near certain critical genes can

lead to cancer.

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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 focused on. CpG islands are short

stretches of DNA rich in the paired bases cytosine and guanine, letters

“C” and “G” in the genetic alphabet. Methyl groups

attach to cytosine bases in DNA.

CpG islands are located near the start sites of genes and help

control a gene’s activity. It’s been thought that planting a

methyl group on an island declares the nearby gene off-limits, blocking

activity.

Researchers have thought of 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.

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 makeups. But no one had mapped out all the places, if

any, where epigenetic marks differ between twins.

Now a team led by Arturas Petronis of the University of Toronto has

explored all of the CpG islands dotting the genome to see which sport

methylation flags. The team compared the methylation patterns of 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 those in fraternal twins, who develop from separate eggs.

And the group found that the amount of variation between monozygotic

twins correlates with the time the embryo split: Counterintuitively,

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 a

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 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 offer a different

perspective. Andrew Feinberg, director of the Epigenetics Center at

Johns Hopkins University in Baltimore, and 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 methylation pattern, indicating which genes are turned

off and which are turned on to build a liver, spleen, brain or other

tissue. Often researchers examine methylation only at CpG islands, but

Feinberg says that most islands are surprisingly 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 team did find characteristic patterns in each tissue type, but

not in CpG islands, where researchers expected. Methylation flagged DNA

in liver, spleen and brain at thousands of places along the CpG island

shores. The shores contained about 76 percent of the methylation flags

shown to be characteristic of specific tissue types.

“This is a discovery that is totally unexpected,” says

Ohlsson. Feinberg’s team has 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 tumors, the team found that methylation

patterns in the shores of the cancer cells were more eroded than those

in healthy colon cells. Feinberg says a breakdown in the patterns may

cause colon stem cells to develop inappropriately, leading to cancer.

Unpublished research by Dag Undlien of the University of Oslo, done

on sabbatical in Feinberg’s lab, indicates that monozygotic twins

share more shore methylation patterns than fraternal 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 maybe a stronger genetic contribution than

is suggested by his data.”

Regardless of who is correct, 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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