Research
Overview
What is O-GlcNAc? O-GlcNAc is the addition of a single N-acetyl-glucosamine residue to serine/threonine residues of proteins found in the cytoplasm, nucleus, or mitochondria (O-GlcNAcylation). Unlike extracellular glycosylation, the sugar residue is not elongated into complex oligosaccharides and is added or removed dynamically in response to cellular stimuli by a single O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA) respectively. O-GlcNAc is involved in many cellular processes such as nutrient sensing, stress response, transcription, translation, cell signaling, and cell cycle regulation.
O-GlcNAc Regulates Mitochondrial Function: Virtually every cell in a multi-cellular organism requires mitochondria to generate ATP or metabolic precursors; unfortunately, alteration of mitochondrial function is synonymous with diseases like Alzheimer’s disease and Cancer. Post-translationalmodifications (PTM) provide mitochondrial proteins with the molecular diversity needed to respond rapidly to changing environmental conditions. The O-GlcNAc post-translational modification regulates mitochondrial function. Alterations in the expression of OGT or OGA have a profound effect on mitochondrial function. We demonstrated that the expression of mitochondrial nuclear encoded genes is dramatically altered when OGT or OGA is over-expressed. Importantly, these changes lowered electron transport chain function and flux through the TCA cycle. Furthermore, we then demonstrated that mitochondrial generation of reactive oxygen species (ROS) is controlled by O-GlcNAc. Together, our data highlights the role of O-GlcNAc in controlling mitochondrial function during times of nutrient excess or stress.
O-GlcNAc Regulates Transcription: Not surprisingly, O-GlcNAc is a key regulator of gene transcription. O-GlcNAc plays a pivotal role in regulating the human g-globin genes by organizing chromatin-remodeling complexes. One mode of g-globin silencing occurs at the GATA binding sites located at -566 or -567 relative to the Ag-globin or Gg-globin CAP sites respectively, and is mediated through the DNA binding moiety of GATA-1 and its recruitment of co-repressor partners, FOG-1 and CHD4 (NuRD complex). Both OGT and OGA associate with the g-globin promoter and alterations in the rate of O-GlcNAc addition and removal control expression of the g-globin. These gene expression changes are mediated by changes in the O-GlcNAcylation status of CHD4. Currently, we are developing novel CRISPR based tools to determine the function of OGT and OGA at cis-regulatory elements within the genome.
- O-GLCNAC HOMEOSTASIS REGULATES MITOCHONDRIAL FUNCTION IN ALZHEIMER'S DISEASE, NIH, PI
- Zhang, Z, Parker, M., P, Graw, S, Novikova, L., V, Fedosyuk, H, Fontes, J., D, Koestler, D., C, Peterson, K., R, Slawson, C. 2019. O-GlcNAc homeostasis contributes to cell fate decisions during hematopoiesis.. The Journal of biological chemistry, 294 (4), 1363-1379
- Zhou, L., T, Romar, R, Pavone, M., E, Soriano-Úbeda, C, Zhang, J, Slawson, C, Duncan, F., E. 2019. Disruption of O-GlcNAc homeostasis during mammalian oocyte meiotic maturation impacts fertilization.. Molecular reproduction and development
- de Queiroz, R., M, Madan, R, Chien, J, Dias, W., B, Slawson, C. 2016. Changes in O-Linked N-Acetylglucosamine (O-GlcNAc) Homeostasis Activate the p53 Pathway in Ovarian Cancer Cells.. The Journal of biological chemistry, 291 (36), 18897-914
- Tan, E., P, McGreal, S., R, Graw, S, Tessman, R, Koppel, S., J, Dhakal, P, Zhang, Z, Machacek, M, Zachara, N., E, Koestler, D., C, Peterson, K., R, Thyfault, J., P, Swerdlow, R., H, Krishnamurthy, P, DiTacchio, L, Apte, U, Slawson, C. 2017. Sustained O-GlcNAcylation reprograms mitochondrial function to regulate energy metabolism.. The Journal of biological chemistry, 292 (36), 14940-14962
- Machacek, Miranda, Saunders, Harmony , Zhang, Zhen , Tan, Ee Phie, Li, J., Li, Tiangang, Villar, Maira, Artigues, Antonio, Lydic, Todd, Cork, Gentry, Slawson, Chad, Fields, Patrick. 2019. Elevated O-GlcNAcylation enhances pro-inflammatory Th17 function by altering the intracellular lipid microenvironment. Journal of Biological Chemistry (294), 8973-8990
