Epigenetics Agouti ALL

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Chromosome

Chromatin

DNA

Diff t l l a

Cell

M th l a a b h d l l that bi d t ifi

DNA METHYLATION HISTONE MODIFICAT

Nucleus

CHANGING CHROMATIN

Found in the nucleus of cells, chromatin is the complex of DNA, RNA, histones and other proteins tmake up chromosomes. A human body contains 200 different types of cells. The roles the cells p their functions and development are determined by when specific genes are turned on or off

Changing theenetic codeth the human genome sequenced andpped, the next step is identifying andciphering the peripheral elements thatect and alter the behavior of genes.e emerging science of epigenetics studiese chemicals and molecules that regulatenes turning them on and off which,turn, makes us what we are. A betterderstanding of these processes

uld lead to new and moreective ways to treatd prevent disease.

Turned on: Modified or loosened by epigenetic factors,chromatin boosts gene expression.

Turned off: DNA tightly bundled around histonesto shut down, its genes unexpressed or turned o

The human genome isan indisputably stun-ning piece of work:25,000 or so genes

containing all of the essentialinstructions for building abeing.

Still, its only a guide.Alone, the genome can-not construct a person.

The book of life requiresa vocabulary of attendantmolecules, compounds andchemicals a biochemicallanguage, so to speak to

help genes write the individu-al story of you.

Altogether, this phenom-enon is called epigenetics. Itsstudy represents one of thecutting edges of bioscience,offering the possibility of not

just curing diseases like can-cer and diabetes, but prevent-ing them altogether.

The human epigenome isthe next frontier of genomicresearch, said Bing Ren, anassociate professor of cellularand molecular medicine atthe University of CaliforniaSan Diego, which recentlyreceived a five-year, $16.6million grant from the federalNational Institutes of Health(NIH) to establish The SanDiego Epigenome Center atthe Ludwig Institute for Can-cer Research on campus.

Ren and colleagues arepartnering with research-ers at the Salk Institute inLa Jolla, the University of

Wisconsin and Cold SpringHarbor Laboratory in New

York. San Diego is one of fourcenters that are part of theNIHs Roadmap Epigenomics

Program, a five-year, $190 mil-

lion effort.Just as the Human Ge-

nome Project provided apicture of the sequence ofgenomes, said Ren, our

work will help create a mapof the processes that impactgene regulation what turnsgenes on and off in orderto improve our understandingof what drives human devel-opment and disease.

It will be a daunting effort,more challenging perhapsthan the genome project,

which involved scientistsaround the world, cost bil-lions of dollars and spannedmore than a decade.

Though no one knows ex-actly how many gene regula-tors there are, researchers doknow they vastly outnumbergenes. This month Ren and

others announced the idecation and mapping of 55,enhancers, short regionDNA that act to boost or ehance gene expression.

More importantly, scientists do not yet fully undestand how genes are regulated by external elementor why.

And finally, there are siply a lot of epigenomes outhere and theyre alwaychanging.

Theres only one geno

Dr. Peter Jones, director othe University of SoutherCalifornia/Norris Comprhensive Cancer Center tothe journalEnvironmentaHealth Perspectives in 200but an epigenome varies

BIoSCIENTISTS FoCUS oN ThE NEw, vASTpoTENTIAL oF EpIGENETICS

Eicentered

The contrast between two genetically identical mice showthe power of epigenetics. When fed a normal diet, Agoutimice with a mutation that makes them yellow and prone toobesity gave birth to obese yellow pups (left). But Agoutis

methyls produced thin brown offspring.Randy Jirtle

SEE Epigenetics

story byScott LaFee,staff Writer graphic byDanieL WieganD,staff neWs artist


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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 imprintinglaboratory 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 Agoutimice 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.


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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,


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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.

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Epigenetics Agouti ALL