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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    • "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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    • "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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    • "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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