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Translating the Histone Code: A Tale of Tails at Stetten Talk

By Alison Davis

News stories appearing over the last year would have everyone believe that scientists have — once and for all — cracked the human genetic code. Indeed, two teams of scientists have already published a draft sequence of our 3-billion-unit jumble of DNA "letters." But the task of thoroughly deciphering the code's protein-making instructions — something our bodies do with ease all the time — is a complicated puzzle that will keep researchers busy for decades to come. Dr. C. David Allis of the University of Virginia will be narrating the latest chapter on how our cells translate pieces of DNA into a meaningful message at this year's DeWitt Stetten Jr. Lecture. Allis will describe his research untangling the functions of chromatin, structures inside our cells that package genes. The talk will be held on Wednesday, Oct. 17 at 3 p.m. in Masur Auditorium, Bldg. 10.

Allis is a pioneer in research that aims to clarify how cells contain and protect their most precious cargo, DNA, in protein-rich assemblies that are collectively called chromatin. In a sense, chromatin acts as a gatekeeper for our genes, regulating access to DNA by cellular equipment that decodes genes.

Dr. C. David Allis

His groundbreaking studies have begun to reveal that a key step in how cells interpret their genetic code involves actually finding certain genes inside chromatin. A cell's gene-decoding machinery is drawn to proteins in chromatin that have been "marked" with a variety of natural chemical tags. Putting on these tags and taking them off, Allis has found, is a critical aspect of targeting a cell's gene-reading activities.

In recent years, Allis' lab has helped to discover several of the cellular systems that carefully balance the chromatin-marking chemical tags, called acetyl, phosphate and methyl groups. These units get attached to histones, the principal protein building blocks of chromatin that wind DNA into a protective spool. For example, he explains, the "aurora kinase" enzyme puts a tag called a phosphate group at a particular spot on the ends, or "tails," of histone proteins. According to Allis, this tag somehow tells the cell that it is time to bundle up its chromatin in time for cell division. This process helps to ensure that the cell's genetic material is separated precisely in half during cell division.

By conveying such a message, genes get turned on — or in some cases, off — Allis says. In the case of cancer cells, inappropriate control of certain growth genes can fuel unchecked cell division. According to Allis, the "chromatin link" to cancer is just now beginning to be appreciated. Indeed, his studies have uncovered that several histone-marking enzymes, like the aurora kinase, actually are revved up in cancer cells, making them an important target for developing future cancer drugs.

Allis first got interested in chromatin more than 20 years ago, while working as a postdoctoral fellow in the lab of Dr. Martin Gorovsky at the University of Rochester. Then and now, Allis has remained committed to studying chromatin via model systems such as the protozoan Tetrahymena, a single-celled ciliate organism that he refers to as an "offbeat pond-water beast."

Offbeat or not, it's also the organism that netted another NIGMS grantee, Dr. Thomas Cech of the University of Colorado at Boulder and the Howard Hughes Medical Institute, the 1989 Nobel prize in chemistry — for figuring out that the genetic material RNA can work as an enzyme.

Scientists like Allis, Cech and countless others use so-called lower organisms like Tetrahymena to address fundamental questions that pervade biology. Such systems are simple, but they retain important similarities to the workings of animal and human cells.

"Forget about what you do in the lab, look at what nature did," says Allis, citing the molecules and cellular processes that recur over and over again throughout the biological kingdom.

He says he is extremely grateful for years of NIH funding to work with "offbeat" model organisms. "The implications for human biology and disease are far-reaching," he says.

Allis earned a bachelor's degree in biology from the University of Cincinnati in 1973 and a doctorate in biology from Indiana University in 1978. He was on the faculty at Baylor College of Medicine from 1981 to 1990, at Syracuse University from 1990 to 1995, and at the University of Rochester from 1995 to 1998. Since 1998, he has been the Harry F. Byrd, Jr. professor of biochemistry and molecular genetics, professor of microbiology, and member of the Center for Cell Signaling at the University of Virginia Health Sciences Center. He has won several awards for both teaching and research, and is an elected member of the American Academy of Arts and Sciences.

NIGMS has supported Allis' work since 1984.

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