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O-GlcNAc cycling: emerging roles in development and epigenetics. | LitMetric

O-GlcNAc cycling: emerging roles in development and epigenetics.

Semin Cell Dev Biol

Laboratory of Cell Biochemistry and Biology, NIDDK, National Institutes of Health, NIH, Bethesda, MD 20892-0850, USA.

Published: August 2010

AI Article Synopsis

  • The hexosamine signaling pathway regulates O-linked N-acetylglucosamine (O-GlcNAc) levels, influencing various cellular processes such as signaling and gene expression, and can be disrupted in diseases like neurodegeneration, cancer, and diabetes.
  • In model organisms, the O-GlcNAc transferase (OGT/Sxc) is crucial for controlling gene repression critical for body plan development, and its associated O-GlcNAcase (OGA) is linked to ancient regulatory gene clusters.
  • This nutrient-sensing pathway may affect epigenetic regulation of gene expression, suggesting that nutritional experiences during pregnancy could have lasting impacts on metabolic health for future generations.

Article Abstract

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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917487PMC
http://dx.doi.org/10.1016/j.semcdb.2010.05.001DOI Listing

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