O-GlcNAc cycling: Emerging roles in development and epigenetics

Laboratory of Cell Biochemistry and Biology, NIDDK, National Institutes of Health, NIH, Bethesda, MD 20892-0850, USA.
Seminars in Cell and Developmental Biology (Impact Factor: 6.27). 08/2010; 21(6):646-54. DOI: 10.1016/j.semcdb.2010.05.001
Source: PubMed


The nutrient-sensing hexosamine signaling pathway modulates the levels of O-linked N-acetylglucosamine (O-GlcNAc) on key targets impacting cellular signaling, protein turnover and gene expression. O-GlcNAc cycling may be deregulated in neurodegenerative disease, cancer, and diabetes. Studies in model organisms demonstrate that the O-GlcNAc transferase (OGT/Sxc) is essential for Polycomb group (PcG) repression of the homeotic genes, clusters of genes responsible for the adult body plan. Surprisingly, from flies to man, the O-GlcNAcase (OGA, MGEA5) gene is embedded within the NK cluster, the most evolutionarily ancient of three homeobox gene clusters regulated by PcG repression. PcG repression also plays a key role in maintaining stem cell identity, recruiting the DNA methyltransferase machinery for imprinting, and in X-chromosome inactivation. Intriguingly, the Ogt gene resides near the Xist locus in vertebrates and is subject to regulation by PcG-dependent X-inactivation. OGT is also an enzymatic component of the human dosage compensation complex. These 'evo-devo' relationships linking O-GlcNAc cycling to higher order chromatin structure provide insights into how nutrient availability may influence the epigenetic regulation of gene expression. O-GlcNAc cycling at promoters and PcG repression represent concrete mechanisms by which nutritional information may be transmitted across generations in the intra-uterine environment. Thus, the nutrient-sensing hexosamine signaling pathway may be a key contributor to the metabolic deregulation resulting from prenatal exposure to famine, or the 'vicious cycle' observed in children of mothers with type-2 diabetes and metabolic disease.

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Available from: John A Hanover, Oct 03, 2015
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    • "A new pathway or molecule identified by IPA Upstream Regulator analyses is MGEA5 (meningioma expressed antigen 5) which was down regulated in large follicles (Figure 6). There is a diverse set of about 600 proteins known to be post-translationally modified by the addition of O-linked N-acetylglucosamine (O-GlcNAc) to their serine and threonine residues by the action of the enzyme O-GlcNAc transferase (OGT/Sxc) [75]. MGEA5 encodes beta-N-acetylglucosaminidase (O-GlcNAcase), whose catalytic activity removes O-GlcNAc from serine and threonine residues in proteins [75]. "
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    • "O-GlcNAcylation is a reversible post-translational modification of serine/threonine that often alternates or competes with protein phosphorylation and is controlled by two enzymes: O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase (OGA) (Hart et al., 2007; Hart et al., 2011) (Fig. 3). O-GlcNAcylation regulates many cellular functions including signaling, gene expression, degradation, and trafficking (Hart et al., 2007) and, interestingly, appears to be particularly sensitive to physiological flux of the UDP-GlcNAc pools (Love et al., 2010). Interestingly, a recent paper by Rilla and collaborators demonstrates the large range of UDP-sugar contents presented by different cell types, and showed a correlation between the expression of different HASes and the UDP-sugars (Rilla et al., 2013). "
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