It’s well known that modern high calorie, sugary diets correlate with increasing rates of diabetes, obesity, neurodegenerative diseases (Alzheimer’s in particular), and cancers. Metabolic dis-regulation is associated and SUSPECT in all of these health problems. There are already over 14,000 records in the E3 Epigenetics publication database containing the word ‘Metabolism’. Researchers hope to show direct epigenetic events, leading to these disease outcomes. One such link, is the post-translational modification (PTM), O-GlcNAcylation.
With the recent development of O-GlcNAc antibodies (thanks partially to grant initiatives by NCI in 2010), and improved mass spec techniques, the study of this unique type of sugar based PTM has become palatable. NIH scientists John A. Hanover, Michael W. Krause and Dona C. Love have just published a Nature review, highlighting the important roles O-GlcNAcylation may play in linking epigenetics to diseases featuring dis-regulated metabolism (1). There have also been a slew of other excellent O-GlcNAc publications this spring. I’d say that O-GlcNAcylation is a trending research area.
The cellular levels of O-GlcNAcylation were originally thought to be minuscule, due to its rapid degradation at cell lysis. As methods improved, levels had been thought to be equivalent to phosphorylation levels, existing throughout cellular compartments. Unexpectedly, recent evidence shows that the O-GlcNAc modification is often much less abundant than protein phosphorylation(2). However, it appears to be targeting a subset of phosphorylated proteins and may be involved in enzymatic activity regulation (3). Notably, GlcNAc sometimes cross-talks with phosphorylation modifications on a shared peptide substrate. The history makes it sound like it’s been tricky work.
O-GlcNAcylation is new-ish player in epigenetics with multiple roles paired with its dynamic response to nutrient availability. O-GlcNAcylation is the covalent attachment of β-D-N-acetylglucosamine (GlcNAc) sugars to a serine or threonine, within a peptide sequence. This reversible modification is added by O‐GlcNAc transferase (OGT) and removed by O‐GlcNAcase (OGA ). These two enzymes interact with transcriptional regulators, histone modifiers, and the transcription enzyme, Pol II. O-GlcNAcylation also marks histones themselves. It is part of the “histone code”. How cellular cycling of O-GlcNAc influences X chormosome inactivation, and some key transcriptional regulatory complexes, are also being investigated. This sugar based epimark will show how our diet can directly influence our gene expression.
With all this sweet talk of O-GlcNAcylation research taking off,… I want to leave you with a funny quote.
“I went to the bank and asked to borrow a cup of money. They said “What for?” I said, “I’m going to buy some sugar.” -Stephen Wright.
1. John A. Hanover, Michael W. Krause & Dona C. Love Bittersweet memories: linking metabolism to epigenetics through O‐GlcNAcylation (2012) Nature.
2. Hannes Hahne1, Amin Moghaddas Gholami1& Bernhard Kuster . Discovery of O-GlcNAc-modified proteins in published large-scale proteome data . (2012) Mol. Cell Proteomics
3. Trinidad et al. Global Identification and Characterization of Both O-GlcNAcylation and Phosphorylation at the Murine Synapse. (2012) The American Society for Biochemistry and Molecular Biology, Inc
Image credit: <a href=’http://www.123rf.com/photo_10354097_refined-sugar-in-glass-cup-isolated-on-white.html’>serezniy / 123RF Stock Photo</a>
Hanover, J., Krause, M., & Love, D. (2012). Post-translational modifications: Bittersweet memories: linking metabolism to epigenetics through O-GlcNAcylation Nature Reviews Molecular Cell Biology, 13 (5), 312-321 DOI: 10.1038/nrm3334