Researchers find evidence of “second genetic code”

Stephanie Gross

C. David Allis

Staff Report

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

In four articles published in the Aug. 10 issue of the journal Science, 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, around which the DNA is coiled, form a structure called chromatin and provide sites where additional gene regulation appears to occur, acting, in effect, as a master “on/off” switch.

C. David Allis, U.Va. Byrd Professor of Biochemistry and Molecular Genetics, explains that the scientific community has known for some time that the location of specific genes within chromatin appears to determine whether that gene is “on” or “off.”  The DNA in our cells is not “naked,” and as a consequence of its form in chromatin, it makes a difference in what kind of chromatin “neighborhood” a particular gene finds itself.

“If a gene is located in a ‘bad neighborhood’, so to speak, it will likely become silenced, and if that gene is a cancer-preventing gene, this change in expression may cause disease,” Allis said.  “If the same gene is located in a good chromatin neighborhood where it’s turned on, then the disease is less likely to be expressed.

Likewise, a gene that may cause the development of a disease like cancer may be located in an area of the chromatin where it’s switched off, and therefore this may be effective for stopping the disease. The most remarkable part is that some changes in expression occur without any changes in the DNA itself, which simply carries our genetic information waiting to be expressed. Our research is attempting to understand what we have referred to as a ‘histone code’ — how chemical changes affecting the histone proteins affect gene expression — and could eventually lead to the development of highly targeted and highly effective therapies for disease control through gene regulation.”

The Science papers describe a process called methylation, wherein a chemical methyl group is added to histones. The studies suggest that exactly where the methylation mark appears in the histone proteins makes a big difference.

Collectively, these studies suggest that methylation of histones can act like a master “on/off” switch that is indexing our genome in ways that we have only begun to appreciate, according to Allis.

“The cell is somehow making choices about using histone methylation to turn a gene on or off,” said Allis, 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 itself. 

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 histone code.”

In their article, “Translating the Histone Code,” the authors discuss how such a code is translated into biological functions.

“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 has co-authored several studies that show evidence that histone methylation is at the heart of this common on/off switch. In a second article in today’s issue of Science, Allis and two scientists at Cold Spring Harbor Laboratory, show that the on-off system works with large blocks of chromatin in yeast. A group at NIH has obtained similar data supporting these conclusions using the expression of blood-forming genes in the chicken for their experiments.

Other experiments suggest that the same system is at work in human cells where it seems to control gene expression phenomena that include X inactivation and imprinting, processes where whole chromosomes or domains within chromosomes are selectively turned off during development.

“Together these data indicate that this switch or indexing system for our genome is most fundamental, existing in even the simplest genetic organisms like yeast, and has not changed dramatically with mammalian evolution,” Allis said. “The link between histone methylation and defects in human imprinting demonstrate clearly that human disease is tied to mistakes made in this marking system.”

“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,” Allis said. “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, stem cell biology and aging, are far-reaching.”