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Flipping the Genetic Switch

Research reveals a second gene code that may be the on-off button for DNA

THURSDAY, Aug. 9, 2001 (HealthDayNews) -- A key part of the mystery surrounding how genes decide our destiny may soon be unraveled, new research suggests.

Four reports that appear in tomorrow's issue of Science point to evidence of a second genetic code that works in concert with DNA, the strands of genetic information that determine major traits in humans. When scientists break that second code, also known as the histone code, it could lead to the prevention of many kinds of diseases, the researchers say.

"It's a long-range indexing system for our genome," says David Allis, the co-author of some of the articles and Byrd Professor of Biochemistry and Molecular Genetics at the University of Virginia. "Once we learn how our human genes are nested in this code, we can find analogs for disease. There's a whole other layer of gene regulation that's outside of the DNA itself. I don't think we can dismiss this anymore."

Shiv Grewal, a co-author of one of the articles and a geneticist at Cold Spring Harbor Laboratory in New York, puts it this way: "It's the code that unlocks the basic code of DNA. It has a major impact on how these pieces of DNA express themselves. The expression of the DNA code depends on the histone code. We're just beginning to understand this; it's just the tip of the iceberg."

For years, Allis explains, scientists have agreed that DNA is the master molecule for all genetic expression. But at the same time, they have dismissed histones -- around which the DNA spirals -- as nothing more than a passive player in gene regulation, simply tidying up the more important DNA. However, scientists could not explain why two organisms with identical DNA would often have genetic differences. They even gave a name to the phenomenon: epigenetics, or any inherited change that can't be accounted for by DNA alone.

What this latest research does is explain a big part of that phenomenon. It shows that histones do play a role in gene regulation, the scientists say. By using a process called methylation on yeast organisms, they found the "tails" of these histones work with different enzymes to loosen or tighten DNA at key junctures so certain genes can be switched on or off. And they seem to communicate with a specific code when carrying out their work, they add.

"This is the biochemical mechanism of gene expression," says Jerry L. Workman, Paul Berg Professor of Biochemistry at Pennsylvania State University. "[This] on-off switch was not well understood. The point is, we didn't know what controlled the epigenetic sequence. So what the histone code does is give us insight into how this works, how the proteins associated with DNA work. Now we're finding out they're working with enzymes to turn genes on and off."

The research could also explain why scientists have encountered problems with cloning because only DNA has been used in efforts to replicate animals. Researchers at MIT recently reported gene-related errors in cloned mice even though the animals appeared to be normal, and they suggested this on-off switching mechanism may be responsible for the abnormalities.

While studying histones, Grewal and his colleagues at Cold Spring Harbor tripped across another element of genetic regulation that they believe has far-reaching implications for understanding of genetic diseases. Within the histone code, they found the regions that turned a gene off were right next to the regions that turned a gene on, but they never mingled. When researchers looked closer, they found what they call "boundary elements," or genetic fences. When they removed these, the two regions spilled over into each other.

"The boundary elements organize the histones, which organize the DNA," Grewal says, adding that these boundary elements are what his group plans to study next. "If you mess with the codes, you're going to have problems. It leads to defects in genetic expression."

Most diseases are caused by flawed proteins, which are created when there is a mistake in the gene-sequencing process, he explains.

As for the overall implications of these most recent findings, Allis thinks one day it may be possible to reduce disease risk simply by turning genes on and off.

"I think we'll be able to get a map of the histone code," he says. "This is going to be a tough one to crack, but we've come a long way in the last five to 10 years. Slowly but surely, new insights are coming from labs all over the country. I can't even think past the next 10 years; it's going that fast."

What To Do

Go here for everything you want to know about histones.

And don't forget to read up on the findings of the Human Genome Project.

Curious as to what the anatomy of the DNA's double helix looks like? Check it out here. And here's a very simple explanation of how genes work.

SOURCES: Interviews with David Allis, Ph.D, Byrd Professor of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville; Shiv Grewal, Ph.D, geneticist, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.; Jerry L. Workman, Ph.D, Paul Berg Professor of Biochemistry, Penn State University, College Station, Pa.; Aug. 10, 2001, Science
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