O-GlcNAc: The Sweet Side of Epigenetics

In 1992 Edmond H. Fischer and Edwin G. Krebs won the Nobel Prize in Physiology or Medicine “for their discoveries concerning reversible protein phoshorylation as a biological regulatory mechanism.” Phosphorylation of proteins can essentially be thought of as the on/off switch that regulates protein activity inside of cells.

It became increasingly clear later on, however, that protein physiology was much more complex than regulation through just a simple on/off phosphorylation switch. It was eventually discovered by Johns Hopkins’ very own Dr. Gerald Hart that a very special sugar called N-acetylglucosamine (GlcNAc) can be added to the same places on proteins where phosphorylation often occurs. The addition of GlcNAc to these sites is now known as the O-GlcNAc modification. O-GlcNAc essentially serves as another layer of control over protein physiology by acting as a sort of “cap” that must be removed before a protein can be phosphorylated. In otherwords, phosphorylation and the O-GlcNAc modification cycle between each other to regulate how many important proteins behave. One amazing feature of the O-GlcNAc modification is the fact that it is performed by only two enzymes, OGT which adds it to proteins and OGA which removes it, and that’s it. This is in stark contrast to protein phosphorylation and dephosphorylation which needs hundreds of different enzymes to perform phosphorylation mechanics.

Fig 1.  Histones are modified by O-GlcNAc.

Fig 1. Histones are modified by O-GlcNAc.

To this day O-GlcNAc cycling remains an enigma, however, emerging evidence continues to mount that illustrates the very important physiological roles for O-GlcNAc. Two of some of the most important concepts within the realm of epigenetics are the modifications of histones and the methylation of DNA. It is now known that histones, which are proteins that help package DNA into the nucleus, are modified by O-GlcNAc 1 (fig 1.). The other major type of epigenetic regulation of gene expression– methylation of DNA–silences genes, but is also a reversible process. Proteins named TETs help to remove methyl groups on DNA to reverse this silencing. Recently it has also been shown that TETs have their activity regulated by O-GlcNAc 2. In otherwords, O-GlcNAc seems to have a very important role in regulating and interacting with two very important physiological mechanisms that write the epigenetic code.

Finally, glucose is most often thought of as fuel for the cell–and this is true–however, the substrate that is required to perform the O-GlcNAc modification (GlcNAc) happens to also be a byproduct of glucose metabolism. Major diseases such as cancer, diabetes, and Alzheimer’s are often associated with altered glucose metabolism and also have profound epigenetic changes. It is quite tempting, therefore, to postulate that O-GlcNAc may be the key that links environment, stress, nutrient availability, and metabolism to changes in epigenetics. Understanding carbohydrate metabolism and O-GlcNAc regulation of epigenetics may one day open new doors that will lead to breakthroughs in regenerative medicine, understanding embryological development, tissue engineering, and treating major diseases.

About the Author: Christopher Saeui is a fourth year Biomedical Engineering PhD student in the Kevin J. Yarema Laboratory for Cell and Carbohydrate Engineering studying the epigenetic and metabolic mechanisms that alter glycosylation in cancer.

1. Sakabe, K., Wang, Z. & Hart, G. W. Beta-N-acetylglucosamine (O-GlcNAc) is part of the histone code. Proc. Natl. Acad. Sci. U. S. A. 107, 19915-19920 (2010).
2. Shi, F. T. et al. Ten-eleven translocation 1 (Tet1) is regulated by O-linked N-acetylglucosamine transferase (Ogt) for target gene repression in mouse embryonic stem cells. J. Biol. Chem. 288, 20776-20784 (2013).

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Epigenetics conference held in beautiful Grand Cayman

Here in the Wirtz lab, we are beginning to connect physical properties of cells with genetic expression. All cells in a Petri dish of the same cell type supposedly have identical DNA sequences. But what makes the cells appear to have different shapes and sizes, and why do some cells respond to stimuli differently from others?

Lectures by poolside are the way to go. Photo by Allison Chambliss.

Lectures by poolside are the way to go. Photo by Allison Chambliss.

These questions have led us to epigenetics, the study of inheritable changes in gene activity that do not involve any changes in the genetic code. These changes most often include the modification of DNA and histones, proteins found in nuclei that the DNA is wound around, by addition or subtraction of functional groups (acetylation, methylation, etc.).

The modifications affect how “open” or “closed” the DNA is and therefore define when and where transcription of DNA to make proteins can occur. I recently attended a fascinating conference on the subject which just so happened to be held on the gorgeous Grand Cayman Island. Here I summarized a few of the conference talks for Epigenie, a science news site focused on epigenetics research.

Story by Allison Chambliss, who is entering her fifth year as a PhD student in the laboratory of Denis Wirtz in the Department of Chemical and Biomolecular Engineering.

Beach breakfast. Photo by Allison Chambliss

Beach breakfast. Photo by Allison Chambliss