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
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.
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
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
“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
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.”