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Epigenetics Agouti ALL

Epigenetics Agouti ALL

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Published by: anuroopmanandhar on Oct 02, 2010
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story by Scott LaFee, staff Writer


graphic by DanieL WieganD, staff neWs artist





he 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 mil-

lion 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

Epigenetics, E2

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

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. DNA

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.

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

Turned off: DNA tightly bundled around histones tends to shut down, its genes unexpressed or turned off.

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.

HISTONE MODIFICATION Different molecules can attach to the dangling “tails” of histones, altering the activity of the DNA wrapped around them.

Histone tail DNA

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.

that makes epigenetics such a potentially powerful medical tool. brown. or identical. they will diverge.” meaning they readily transferred a methyl group (a carbon atom attached to three hydrogen atoms) to other substances. say researchers. Agouti mice with a mutation that makes them yellow and prone to obesity gave birth to obese yellow pups (left). overweight pups.” The contrast between two genetically identical mice shows the power of epigenetics. normalsized pups. however. twins are people born from a single fertilized egg. Though genetically identical. divergent lifestyles. but yellow Agouti mice fed a diet supplemented with methyl donors produced thin.” Mice and men Monozygotic. yellow Agouti mice given a normal diet gave birth to typical yellow. are due to epigenetic factors. The experiment was a revelation because it showed a permanent physical change caused by an external influence (nutrition) without alteration of the relevant gene. It's what happens to that DNA that makes us what we are. . choline and vitamin B-12. Jirtle fed half of the Agouti yellow lab mice a normal rodent diet. These mice have an extra piece of DNA in the Agouti gene. When fed a normal diet. In 2003. which makes them yellow. These differences. Randy Jirtle.each and every tissue. But Agoutis fed methyls produced thin brown offspring. The other half received a special diet supplemented with molecules known as “methyl donors. The results were visually unambiguous.” It is that variability and individuality. in scientific parlance – and yet over time. the methyl donors were nutrients like folic acid. In this case. They share the same package of genetic material – a genotype. developing characteristics and conditions that create their own contrasting “phenotypes. We are all born with essentially the same DNA. obese and prone to disease. suffer from diabetes or develop schizophrenia while the other twin does not. (Randy Jirtle) One twin may become obese. a professor of radiation oncology and director of the epigenetics and imprinting laboratory at Duke University. 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. A well-known epigenetics experiment makes the point more specifically. These differences often deepen and sharpen with time or if twins lead separate. and colleagues reported the results of tests with Agouti yellow mice.

a professor of pharmacology and therapeutics at McGill University School of Medicine. too. It was. Poking out from the histones are molecular tails to which epigenetic molecules can attach. McGill scientists have found that pregnant women send chemical signals to their unborn children indicating whether life is calm or stressful. though how exactly is far from fully understood. That's where epigenetics comes in. “When we look at toxicology. with DNA tightly wrapped around them. mental illness and autism. added Jirtle. are all determined by when specific genes are turned on or off. The cells' diverse roles and functions. Another basic epigenetic process called histone modification seems to encourage it.” 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. all containing the same DNA. diabetes. the process involved in the Jirtle lab's mouse experiment.” said Moshe Szyf. but animal experiments have shown that young rodents who experienced positive interaction with their mothers exhibited beneficial epigenetic traits that persisted into adulthood. DNA methylation appears to repress gene activity. When they do. obesity.” said Rob Waterland. how and when they develop.“Our study demonstrates how early environmental factors can alter gene expression without mutating the gene itself. known or suspected. DNA would be unwieldy: Each nucleated human cell contains almost 6 feet of DNA. pesticides. “I think that what we are starting to see is that the social environment is much more powerful than the chemical environment. Loose genes The epigenome is essential to life. DNA tends to loosen. . nutrients. from hormones. Perhaps the best known is DNA methylation. who was a research fellow in the Jirtle laboratory at the time. viruses and bacteria to heavy metals. The human body boasts about 210 known types of cells. Histones are proteins that behave like tiny spools. Research at McGill University in Canada suggests the social environment plays a role. There are a lot of factors. The big challenge is pinpointing what individual epigenetic factors do to specific genes. For example. These signals affect DNA methylation in the developing brain and peripheral cells. Researchers have identified a handful of biochemical processes. which promotes gene expression. “an example of nature via nurture. Without histones. It's unclear to what extent maternal stress negatively affects unborn life. tobacco smoke and other toxins.

They hope to create a blood test to spot this epigenetic change so that patients can be treated before tumors actually form.we always consider toxicology as chemicals. they will be able to rewrite (or at least reread) the “book of life” in ways that will benefit everyone. but I think that social environment can be as toxic as the chemical environment. Broad advances. though.” Ultimately. will come as scientists flesh out and translate the language of epigenetics. . the power and promise of epigenomics lies in its use as a diagnostic tool that could allow doctors to spot medical issues early. said Ren. if not more so. At that point. Cancer research is leading the way. maybe before they even become problematic. Researchers recently identified a single gene called Septin 9 in which DNA methylation occurs very early in colorectal cancer development.

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