Article

Dynamic O-GlcNAc cycling at promoters of Caenorhabditis elegans genes regulating longevity, stress, and immunity.

National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0851, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 04/2010; 107(16):7413-8. DOI: 10.1073/pnas.0911857107
Source: PubMed

ABSTRACT Nutrient-driven O-GlcNAcylation of key components of the transcription machinery may epigenetically modulate gene expression in metazoans. The global effects of GlcNAcylation on transcription can be addressed directly in C. elegans because knockouts of the O-GlcNAc cycling enzymes are viable and fertile. Using anti-O-GlcNAc ChIP-on-chip whole-genome tiling arrays on wild-type and mutant strains, we detected over 800 promoters where O-GlcNAc cycling occurs, including microRNA loci and multigene operons. Intriguingly, O-GlcNAc-marked promoters are biased toward genes associated with PIP3 signaling, hexosamine biosynthesis, and lipid/carbohydrate metabolism. These marked genes are linked to insulin-like signaling, metabolism, aging, stress, and pathogen-response pathways in C. elegans. Whole-genome transcriptional profiling of the O-GlcNAc cycling mutants confirmed dramatic deregulation of genes in these key pathways. As predicted, the O-GlcNAc cycling mutants show altered lifespan and UV stress susceptibility phenotypes. We propose that O-GlcNAc cycling at promoters participates in a molecular program impacting nutrient-responsive pathways in C. elegans, including stress, pathogen response, and adult lifespan. The observed impact of O-GlcNAc cycling on both signaling and transcription in C. elegans has important implications for human diseases of aging, including diabetes and neurodegeneration.

Download full-text

Full-text

Available from: Salil Kumar GHosh, Jun 20, 2015
1 Follower
 · 
180 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The complexity of the genome is regulated by epigenetic mechanisms, which act on the level of DNA, histones, and nucleosomes. Epigenetic machinery is involved in various biological processes, including embryonic development, cell differentiation, neurogenesis, and adult cell renewal. In the last few years, it has become clear that the number of players identified in the regulation of chromatin structure and function is still increasing. In addition to well-known phenomena, including DNA methylation and histone modification, new, important elements, including nucleosome mobility, histone tail clipping, and regulatory ncRNA molecules, are being discovered. The present paper provides the current state of knowledge about the role of 16 different histone post-translational modifications, nucleosome positioning, and histone tail clipping in the structure and function of chromatin. We also emphasize the significance of cross-talk among chromatin marks and ncRNAs in epigenetic control.
    Neurotoxicity Research 12/2014; 27(2). DOI:10.1007/s12640-014-9508-6 · 3.15 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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.
    Seminars in Cell and Developmental Biology 08/2010; 21(6):646-54. DOI:10.1016/j.semcdb.2010.05.001 · 5.97 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: O-GlcNAcylation is an abundant nutrient driven modification linked to cellular signaling and regulation of gene expression. Utilizing precursors derived from metabolic flux, O-GlcNAc functions as a homeostatic regulator. The enzymes of O-GlcNAc cycling, OGT and O-GlcNAcase act in mitochondria, the cytoplasm, and the nucleus in association with epigenetic 'writers' and 'erasers.' of the histone code. Both O-GlcNAc and O-phosphate modify repeats within the RNA polymerase II carboxylterminal domain (CTD). By communicating with the histone and CTD codes, O-GlcNAc cycling provides a link between cellular metabolic status and the epigenetic machinery. Thus, O-GlcNAcylation is poised to influence trans-generational epigenetic inheritance.