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: 9.67). 04/2010; 107(16):7413-8. DOI: 10.1073/pnas.0911857107
Source: PubMed


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.

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Available from: Salil Kumar GHosh, Oct 05, 2015
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    • "The H3T32glc may be an interesting chromatin marker contributing to metabolism and insulin signaling. Moreover, ChIP-seq studies revealed that proteins binding O-GlcNAcylated chromatin regulate transcription of genes associated with metabolism and aging (Love et al. 2010). More recently, it was shown that TET2 and TET3 interact with OGT and target it to chromatin (Chen et al. 2013). "
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    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 · 3.54 Impact Factor
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    • "In 2011, Myers et al. confirmed the link between OGT and polycomb group proteins in mammals by showing that the polycomb repressive complex 2 is required to maintain normal levels of OGT and for correct cellular distribution of O-GlcNAcylation (Myers et al., 2011). Deep sequencing technology established that OGT, OGA, and O-GlcNAcylation are enriched at the active site of transcription in thousands of genes in both human and in C. elegans (Deplus et al., 2013; Love et al., 2010). O-GlcNAcylation regulates many RNA polymerase II transcription factors. "
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    ABSTRACT: The nutrient sensor, O-linked N-acetylglucosamine (O-GlcNAc), cycles on and off nuclear and cytosolic proteins to regulate many cellular processes, including transcription and signaling. Dysregulated O-GlcNAcylation and its interplay with phosphorylation contribute to the etiology of diabetes, cancer, and neurodegeneration. Herein, we review recent findings about O-GlcNAc's regulation of cell physiology.
    Cell Metabolism 08/2014; 20(2):208-213. DOI:10.1016/j.cmet.2014.07.014 · 17.57 Impact Factor
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    • "Indeed, O-GlcNAcylation has been found associated with chromatin preparations (Kelly and Hart, 1989), on transcription factors (Ozcan et al., 2010), on RNA polymerase II (Comer and Hart, 2001; Ranuncolo et al., 2012), and on histones H2A, H2B, H3, and H4 (Sakabe et al., 2010). Our lab has also shown that O-GlcNAcylation is particularly abundant on the promoter region in C. elegans (Love et al., 2010). Furthermore, OGT is also associated with TET (Ten-Elevent Translocation) proteins, responsible for demethylation of DNA and activation of transcription (Mariappa et al., 2013). "
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    ABSTRACT: O-GlcNAc Transferase (OGT) catalyzes protein O-GlcNAcylation, an abundant and dynamic nuclear and cytosolic modification linked to epigenetic regulation of gene expression. The steady-state levels of O-GlcNAc are influenced by extracellular glucose concentrations suggesting that O-GlcNAcylation may serve as a metabolic sensor. Intriguingly, human OGT is located on the X-chromosome (Xq13) close to the X-inactivation center (XIC), suggesting that OGT levels may be controlled by dosage compensation. In human female cells, dosage compensation is accomplished by X-inactivation. Long noncoding RNAs and polycomb repression act together to produce an inactive X chromosome, or Barr body. Given that OGT has an established role in polycomb repression, it is uniquely poised to auto-regulate its own expression through X-inactivation. In this study, we examined OGT expression in male, female and triple-X female human fibroblasts, which differ in the number of inactive X chromosomes (Xi). We demonstrate that OGT is subjected to random X-inactivation in normal female and triple X cells to regulate OGT RNA levels. In addition, we used chromatin isolation by RNA purification (ChIRP) and immunolocalization to examine O-GlcNAc levels in the Xi/Barr body. Despite the established role of O-GlcNAc in polycomb repression, OGT and target proteins bearing O-GlcNAc are largely depleted from the highly condensed Barr body. Thus, while O-GlcNAc is abundantly present elsewhere in the nucleus, its absence from the Barr body suggests that the transcriptional quiescence of the Xi does not require OGT or O-GlcNAc.
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