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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    • "Although the enzymes of O-GlcNAc cycling are highly conserved in metazoa, the pathway has been exploited in different ways during evolution (Love et al., 2010b). It is clear that in invertebrates, O-GlcNAc plays a key role in regulating signaling and the regulation of Hox gene expression. "
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    ABSTRACT: Unlike the complex glycans decorating the cell surface, the O-linked β-N-acetyl glucosamine (O-GlcNAc) modification is a simple intracellular Ser/Thr-linked monosaccharide that is important for disease-relevant signaling and enzyme regulation. O-GlcNAcylation requires uridine diphosphate-GlcNAc, a precursor responsive to nutrient status and other environmental cues. Alternative splicing of the genes encoding the O-GlcNAc cycling enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) yields isoforms targeted to discrete sites in the nucleus, cytoplasm, and mitochondria. OGT and OGA also partner with cellular effectors and act in tandem with other posttranslational modifications. The enzymes of O-GlcNAc cycling act preferentially on intrinsically disordered domains of target proteins impacting transcription, metabolism, apoptosis, organelle biogenesis, and transport.
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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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