Evidence of Second Genetic Code

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CONTACT: Catherine Seigerman WolzU.Va. Health System Media Relations434-924-5679

U.VA. RESEARCHERS FIND EVIDENCE OF SECOND GENETIC CODE

CHARLOTTESVILLE, Va., August 10 -- Sequencing and mapping the human genome was the first essential step for scientists to study where genes for diseases like cancer are located. But in studies to identify the complex factors that make those genes active or inactive, molecular genetic researchers at the University of Virginia have discovered a new area outside the DNA itself that may show existence of another type of genetic code.

In four articles published today in Science magazine, U.Va. researchers and collaborators at the National Institutes of Health (NIH) and Cold Spring Harbor Laboratory in New York, as well as the Research Institute of Molecular Pathology at the Vienna Biocenter in Austria, describe how proteins called histones, which are coiled around the DNA and form a structure called chromatin, provide sites where additional gene regulation appears to occur.

The histones, like all proteins, are made up of amino acids. At the end of each histone's structure, there is a long strand called a "tail" where lysine residues, a type of amino acid, are often closely located. For example, in a histone H3, the object of the U.Va. studies, two highly conserved -- found in a wide range of organisms -- lysines exist at the fourth (K4) and ninth (K9) positions. Through a process called histone methylation, a chemical methyl group is enzymatically added to K4 or K9. Collectively, these studies suggest that methylation of histones in chromatin, like the genes, acts like a master "on/off" switch.

"The cell is somehow making choices about using methylation to turn a gene on or off," said C. David Allis, Byrd Professor of Biochemisty and Molecular Genetics at U.Va., who co-authored several of the research articles along with a review on this topic with Thomas Jenuwein of the Vienna Biocenter. "We believe that what is telling the cell to make those choices is an overall code that may significantly extend the information potential of the genetic DNA code. For some time, we have known that there is more to our genetic blueprint than DNA itself. We are excited that we are beginning to decipher a new code, what is referred to as an epigenetic code."

In their article, "Translating the Histone Code," the authors discuss how such a code is "read" and translated into biological functions. These include methylation and other chemical changes that can determine major genetic traits in humans, such as disease risk.

"If we know how to control which genes we want to turn on or off, we might be able to reduce disease risk," Allis said. "For example, we could turn off genes that promote tumor growth to help prevent cancer development, and turn on other genes that suppress tumors."

Allis and other researchers have co-authored several studies that show evidence that histone methylation is at the heart of this highly conserved molecular on/off switch. In a second article in today's issue of Science, co-authored by Allis and Ken-ichi Noma and Shiv I.S. Grewal, two scientists at Cold Spring Harbor Laboratory, the on-off system of K4 and K9 is shown to work with large blocks of chromatin in yeast. Supporting data has been obtained by a group at the NIH lead by Gary Felsenfeld. "Together this data indicates that this switch and indexing system for our genome is most fundamental, existing in even the simplest genetic organisms like yeast, and has not changed with mammalian evolution," Allis said.

"Clear evidence is beginning to link alterations in chromatin structure to cell cycle progression, DNA replication, DNA damage and its repair, recombination and overall chromosome stability. If this histone code hypothesis is correct and an on/off master switch exists for genes that are housed in chromatin, the implications for human biology and disease, including cancer and aging, are far-reaching," Allis said.

# # #August 3, 2001