Yelo
Red Blue
HIPPOS: FAMILY TREE
Researchers reporting in the journal Nature say DNA evidence in-
dicates the hippopotamus is the closest living relative of the whale.
Their conclusion disputes an earlier report, based on fossil evidence,
Quest
that argued hippos are more closely related to pigs than to whales.
currents
science
Nucleus
Changing the
genetic code
With the human genome sequenced and
mapped, the next step is identifying and
deciphering the peripheral elements that
affect and alter the behavior of genes.
The emerging science of epigenetics studies
the chemicals and molecules that regulate
genes — turning them on and off — which,
in turn, makes us what we are. A better
understanding of these processes
could lead to new and more
effective ways to treat
and prevent disease.
Histone tail
Histones are key proteins that act like
spools, with DNA tightly wrapped around
them. Without histones, unwound DNA would
be extremely long: each nucleated human
cell contains almost 6 feet of DNA.
E1 QUEST 3.30.09
K E1 QUEST 3.30.09
● arts ● tv
Bioscientists focus on the new, vast
potential of epigenetics
Epicentered
story by Scott LaFee, Staff Writer
T
he human genome is
an indisputably stun-
ning piece of work:
Cell 25,000 or so genes
containing all of the essential
instructions for building a
being.
Still, it’s only a guide.
Alone, the genome can-
not construct a person.
The “book of life” requires
a vocabulary of attendant
molecules, compounds and
chemicals — a biochemical
Chromosome language, so to speak — to
help genes write the individu-
al story of you.
Altogether, this phenom-
enon is called epigenetics. Its
study represents one of the
cutting edges of bioscience,
offering the possibility of not
just curing diseases like can-
cer and diabetes, but prevent-
ing them altogether.
“The human epigenome is
the next frontier of genomic
research,” said Bing Ren, an
associate professor of cellular
and molecular medicine at
the University of California
San Diego, which recently
received a five-year, $16.6
million grant from the federal
National Institutes of Health
(NIH) to establish The San
Diego Epigenome Center at
Chromatin the Ludwig Institute for Can-
cer Research on campus.
Ren and colleagues are
partnering with research-
ers at the Salk Institute in
La Jolla, the University of
Wisconsin and Cold Spring
Harbor Laboratory in New
York. San Diego is one of four
centers that are part of the
NIH’s Roadmap Epigenomics
Program, a five-year, $190 mil-
CHANGING CHROMATIN
Found in the nucleus of cells, chromatin is the complex of DNA, RNA, histones and other proteins that
make up chromosomes. A human body contains 200 different types of cells. The roles the cells play
— their functions and development — are determined by when specific genes are turned on or off.
DNA
Turned on: Modified or loosened by epigenetic factors,
chromatin boosts gene expression.
DNA METHYLATION
Methyls are carbon-hydrogen molecules that bind to specific
parts of DNA strands, repressing gene activity. Exposure of
DNA to methyls is believed to play an important role in
biological development because it restricts genetic information
that will be passed along when cells divide and multiply.
( Yellowplate)
(Cyan
(Magenta
(Black plate)
plate)
plate)
( Yellowplate)
(Cyan
(Magenta
(Black plate)
plate)
plate)
Monday
March 30, 2009
E
The San Diego
Union-Tribune
INSIDE
comics e4, 5, 6
JURY SERVICE: LINGERING EFFECTS
dear abby e7
University of Leicester researchers report that jurors exposed
to harrowing and gruesome evidence may later experience EUREKA! e2
symptoms of post-traumatic stress disorder. The study found
stargazer e2
that female jurors are more vulnerable, particularly if the trial
covers material that resonates with their own lives. TELEVISION e8
● graphic BY Daniel Wiegand, Staff news artist
lion effort. others announced the identifi-
“Just as the Human Ge- cation and mapping of 55,000
nome Project provided a “enhancers,” short regions of
picture of the sequence of DNA that act to boost or en-
genomes,” said Ren, “our hance gene expression.
work will help create a map More importantly, scien- In the title role of the San
of the processes that impact tists do not yet fully under- Diego Opera’s production of
gene regulation — what turns stand how genes are regu- “Rigoletto,” baritone Lado
genes on and off — in order lated by external elements, Ataneli gets some bad news
to improve our understanding or why. — some very, very bad news.
John R. McCutchen / Union-Tribune
of what drives human devel- And finally, there are sim-
opment and disease.” ply a lot of epigenomes out
It will be a daunting effort, there — and they’re always
more challenging perhaps changing. OPERA REVIEW
‘Rigoletto’
than the genome project, “There’s only one genome,”
which involved scientists Dr. Peter Jones, director of
around the world, cost bil- the University of Southern
has many
lions of dollars and spanned California/Norris Compre-
more than a decade. hensive Cancer Center told
Though no one knows ex- the journal Environmental
actly how many gene regula- Health Perspectives in 2006,
of the right
tors there are, researchers do but “an epigenome varies in
know they vastly outnumber
genes. This month Ren and Epigenetics, E2
ingredients
see
By Marcus Overton
Giuseppe Verdi’s lifelong ad-
miration for Shakespeare was
primarily due not to the great
playwright’s use of language
(Verdi probably read the plays
in Italian translations), but to
Shakespeare’s acute insights
into human personality.
In his operas, Verdi strove
to create characters of Shake-
spearean psychological com-
plexity. And like Shakespeare,
Verdi refused to sit in judgment
on his creations, even when
their own mixture of faults and
The contrast between two genetically identical mice shows virtues caused their suffering
the power of epigenetics. When fed a normal diet, Agouti and downfall.
mice with a mutation that makes them yellow and prone to Verdi also worked to gain
obesity gave birth to obese yellow pups (left). But Agoutis fed Shakespeare’s mastery in mix-
methyls produced thin brown offspring. Randy Jirtle ing genres — tragedy and com-
edy, romance and conflict, the
earthy and the spiritual.
“Rigoletto” — which con-
.
tinued San Diego Opera’s
International Season in the
first of five performances at
the Civic Theatre on Saturday
— is a complex work in this
Shakespearean way, and the
challenges its interpreters face
grow out of the depth of its
characters, the layered irony
Turned off: DNA tightly bundled around histones tends
on which its dramatic action
to shut down, its genes unexpressed or turned off. turns, and Verdi’s mixture of
comedy, tragedy and mid-19th-
century melodrama.
In British designer Carl
Toms’ handsome sets and
HISTONE MODIFICATION lavish costumes, beautifully
Different molecules can framed by Michael Whitfield’s
attach to the dangling lighting design, San Diego Op-
“tails” of histones, altering era’s production contains many
the activity of the DNA of the elements that could raise
wrapped around them. it to Shakespearean heights.
Unfortunately, the musical
and dramatic alchemy that
could combine those elements
with conviction, craft and nu-
ance is often missing.
Lotfi Mansouri’s stage direc-
tion veers between unfocused
busyness (in the first act, the
Duke’s swift seduction of
Countess Ceprano all but disap-
pears among the hard-working
dancers and gossiping court-
iers), and aimless wandering in
the crucial two- and three-per-
son scenes where singers need
SEE ‘Rigoletto,’ E3
DNA
DETAILS
Verdi’s “Rigoletto”
San Diego Opera
When: Repeats Tuesday and
April 8 at 7 p.m.; Friday at 8 p.m.;
April 5 at 2 p.m.
Where: Civic Theatre,
1200 Third Ave., downtown
Tickets: $35-$200
Phone: (619) 533-7000
SOURCES: UCSD; NOVA
Online: sdopera.com
each and every tissue.”

It is that variability and individuality, however, that makes epigenetics such a potentially
powerful medical tool. We are all born with essentially the same DNA. It's what happens
to that DNA that makes us what we are.

Said Ren: “Such modifications to the genetic blueprint may provide part of the answer to
why some people are more susceptible to disease than others.”

Mice and men

Monozygotic, or identical, twins are people born from a single fertilized egg. They share
the same package of genetic material – a genotype, in scientific parlance – and yet over
time, they will diverge, developing characteristics and conditions that create their own
contrasting “phenotypes.”

The contrast between two genetically identical mice shows the power of epigenetics.
When fed a normal diet, Agouti mice with a mutation that makes them yellow and prone
to obesity gave birth to obese yellow pups (left). But Agoutis fed methyls produced thin
brown offspring. (Randy Jirtle)

One twin may become obese, suffer from diabetes or develop schizophrenia while the
other twin does not. These differences often deepen and sharpen with time or if twins
lead separate, divergent lifestyles. These differences, say researchers, are due to
epigenetic factors.

A well-known epigenetics experiment makes the point more specifically. In 2003, Randy
Jirtle, a professor of radiation oncology and director of the epigenetics and imprinting
laboratory at Duke University, and colleagues reported the results of tests with Agouti
yellow mice.

These mice have an extra piece of DNA in the Agouti gene, which makes them yellow,
obese and prone to disease. Jirtle fed half of the Agouti yellow lab mice a normal rodent
diet. The other half received a special diet supplemented with molecules known as
“methyl donors,” meaning they readily transferred a methyl group (a carbon atom
attached to three hydrogen atoms) to other substances. In this case, the methyl donors
were nutrients like folic acid, choline and vitamin B-12.

The results were visually unambiguous. Though genetically identical, yellow Agouti
mice given a normal diet gave birth to typical yellow, overweight pups, but yellow
Agouti mice fed a diet supplemented with methyl donors produced thin, brown, normal-
sized pups.

The experiment was a revelation because it showed a permanent physical change caused
by an external influence (nutrition) without alteration of the relevant gene.
“Our study demonstrates how early environmental factors can alter gene expression
without mutating the gene itself,” said Rob Waterland, who was a research fellow in the
Jirtle laboratory at the time.

It was, added Jirtle, “an example of nature via nurture.”

The implications may be huge for human health because scientists suspect epigenetics is
a key reason why people are more or less susceptible to afflictions like cancer, obesity,
diabetes, mental illness and autism.

Loose genes

The epigenome is essential to life. The human body boasts about 210 known types of
cells, all containing the same DNA. The cells' diverse roles and functions, how and when
they develop, are all determined by when specific genes are turned on or off.

That's where epigenetics comes in, though how exactly is far from fully understood.
Researchers have identified a handful of biochemical processes. Perhaps the best known
is DNA methylation, the process involved in the Jirtle lab's mouse experiment.

DNA methylation appears to repress gene activity. Another basic epigenetic process
called histone modification seems to encourage it.

Histones are proteins that behave like tiny spools, with DNA tightly wrapped around
them. Without histones, DNA would be unwieldy: Each nucleated human cell contains
almost 6 feet of DNA.

Poking out from the histones are molecular tails to which epigenetic molecules can attach.
When they do, DNA tends to loosen, which promotes gene expression.

The big challenge is pinpointing what individual epigenetic factors do to specific genes.
There are a lot of factors, known or suspected, from hormones, nutrients, viruses and
bacteria to heavy metals, pesticides, tobacco smoke and other toxins.

Research at McGill University in Canada suggests the social environment plays a role,
too. For example, McGill scientists have found that pregnant women send chemical
signals to their unborn children indicating whether life is calm or stressful. These signals
affect DNA methylation in the developing brain and peripheral cells.

It's unclear to what extent maternal stress negatively affects unborn life, but animal
experiments have shown that young rodents who experienced positive interaction with
their mothers exhibited beneficial epigenetic traits that persisted into adulthood.

“I think that what we are starting to see is that the social environment is much more
powerful than the chemical environment,” said Moshe Szyf, a professor of pharmacology
and therapeutics at McGill University School of Medicine. “When we look at toxicology,
we always consider toxicology as chemicals, but I think that social environment can be as
toxic as the chemical environment, if not more so.”

Ultimately, the power and promise of epigenomics lies in its use as a diagnostic tool that
could allow doctors to spot medical issues early, maybe before they even become
problematic.

Cancer research is leading the way. Researchers recently identified a single gene called
Septin 9 in which DNA methylation occurs very early in colorectal cancer development.
They hope to create a blood test to spot this epigenetic change so that patients can be
treated before tumors actually form.

Broad advances, though, will come as scientists flesh out and translate the language of
epigenetics.

At that point, said Ren, they will be able to rewrite (or at least reread) the “book of life”
in ways that will benefit everyone.