The missing link that spans the gap between the genes and environment could be a sugar – in this case, a special one that regulates histone 3, part of the DNA backbone, said researchers from Baylor College of Medicine and the University of Georgia in a report that appears online in the Journal of Biological Chemistry.
The sugar in question is called beta-N-acetylglucosamine or O-GlcNAc, said Dr. Richard Sifers, professor of Pathology and Immunology at BCM, and corresponding author of the report. In work led by Dr. Jerry Fong, then a graduate student at BCM, the researchers found where the sugar O-GlcNAc is attached to histone 3, one of the protein "spools" around which DNA in the cells wraps. Researchers at the Complex Carbohydrate Research Center at the University of Georgia in Athens helped identify the sugar using a highly refined form of mass spectrometry.
"It was already known that phosphorylation (the addition of a phosphate molecule) on histone 3 was necessary for cells to enter mitosis (cell division)," said Sifers. "We found that O-GlcNAc can prevent phosphorylation. When O-GlcNAc is present, there is no phosphorylation and cells have trouble dividing."
"This shows how your nutritional status can affect the replication of your genome, and this is also the case for gene expression," said Sifers. "If your cells have lots of sugars and energy, they make more O-GlcNAc and more proteins are O-GlcNAcylated. In the case of histone 3, the addition of O-GlcNAc can hinder cell division. We hypothesize that this is a missing link where nutrition can affect gene expression through O-GlcNAcylation."
He thinks there are probably other nutrition-mediated modifications that can have a profound influence on biology.
"This means that we have a DNA "script" that is not always going to be read the same way," said Sifers, who is also a professor of molecular and cellular biology and molecular physiology and biophysics at BCM. "We always refer to the dilemma of nature vs. nurture. How does the environment influence the expression of the fixed genetic code? We think this may be one way to couple specific aspects of biology to one's nutritional status."
"Others have already demonstrated that O-GlcNAcylation plays a fundamental role in diseases such as diabetes and cancer," he said.
Learning how the sugar affects cell division might give new clues about possible treatments for those diseases.
"For many decades, scientists have been examining DNA as the biological 'roster' in the big game of biology. Now, many scientists are pursuing functional genomics in which proteins are examined as the actual 'players'. Sugars are added to proteins to modulate them as a means to 'fine tune' biological processes. For example, when a protein is made in the cell, it must be folded correctly and delivered to the right place. The addition of sugars can participate in this process. This level of fine tuning is necessary for normal biology to take place."
Others who took part in this report include Brenda L. Nguyen and Dr. Shujuan Pan of the Department of Pathology and Immunology at BCM, the late Dr. Estela E. Medrano of the Huffington Center on Aging at BCM, and Drs. Robert Bridger and Lance Wells of the University of Georgia.
Funding for this work came from the National Institutes of Health.