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[genet-news] SCIENCE & GENES: Bioscientists focus on the new, vast potential of epigenetics

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SOURCE: San Diego Union - Tribune, USA

AUTHOR: Scott LaFee


DATE:   30.03.2009

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The human genome is an indisputably stunning piece of work: 25,000 or so genes containing all of the essential instructions for building a being.

Still, it?s only a guide. Alone, the genome cannot construct a person. The ?book of life? requires a vocabulary of attendant molecules, compounds and chemicals ? a biochemical language, so to speak ? to help genes write the individual story of you.

Altogether, this phenomenon is called epigenetics. Its study represents one of the cutting edges of bioscience, offering the possibility of not just curing diseases like cancer and diabetes, but preventing 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 the Ludwig Institute for Cancer Research on campus.

Ren and colleagues are partnering with researchers 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 million effort.

?Just as the Human Genome Project provided a picture of the sequence of genomes,? said Ren, ?our work will help create a map of the processes that impact gene regulation ? what turns genes on and off ? in order to improve our understanding of what drives human development and disease.?

It will be a daunting effort, more challenging perhaps than the genome project, which involved scientists around the world, cost billions of dollars and spanned more than a decade.

Though no one knows exactly how many gene regulators there are, researchers do know they vastly outnumber genes. This month Ren and others announced the identification and mapping of 55,000 ?enhancers,? short regions of DNA that act to boost or enhance gene expression.

More importantly, scientists do not yet fully understand how genes are regulated by external elements, or why.

And finally, there are simply a lot of epigenomes out there ? and they?re always changing.

?There?s only one genome,? Dr. Peter Jones, director of the University of Southern California/Norris Comprehensive Cancer Center told the journal Environmental Health Perspectives in 2006, but ?an epigenome varies in 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.



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