Drosophila O
 -GlcNAc transferase (OGT) is encoded by the
 Polycomb
 group (PcG) gene,
 super sex combs
 (
 sxc
 )

Sinclair, Donald A. R.; Syrzycka, Monika; Macauley, Matthew S.; Rastgardani, Tara; Komljenović, Ivana; Vocadlo, David J.; Brock, Hugh W.; Honda, Barry M.

doi:10.1073/pnas.0904638106

Cited by 214 publications

(209 citation statements)

References 41 publications

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“…3). This and other results of the present study support previous observations that OGT and EZH2/PRC2 are functionally associated with each other (34,35,37). Nevertheless, discrepancy still exists.…”

Section: Discussionsupporting

confidence: 86%

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O-GlcNAcylation regulates EZH2 protein stability and function

Chu

Yeh

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

203

204

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O-linked N-acetylglucosamine (GlcNAc) transferase (OGT) is the only known enzyme that catalyzes the O-GlcNAcylation of proteins at the Ser or Thr side chain hydroxyl group. OGT participates in transcriptional and epigenetic regulation, and dysregulation of OGT has been implicated in diseases such as cancer. However, the underlying mechanism is largely unknown. Here we show that OGT is required for the trimethylation of histone 3 at K27 to form the product H3K27me3, a process catalyzed by the histone methyltransferase enhancer of zeste homolog 2 (EZH2) in the polycomb repressive complex 2 (PRC2). H3K27me3 is one of the most important histone modifications to mark the transcriptionally silenced chromatin. We found that the level of H3K27me3, but not other H3 methylation products, was greatly reduced upon OGT depletion. OGT knockdown specifically down-regulated the protein stability of EZH2, without altering the levels of H3K27 demethylases UTX and JMJD3, and disrupted the integrity of the PRC2 complex. Furthermore, the interaction of OGT and EZH2/PRC2 was detected by coimmunoprecipitation and cosedimentation experiments. Importantly, we identified that serine 75 is the site for EZH2 OGlcNAcylation, and the EZH2 mutant S75A exhibited reduction in stability. Finally, microarray and ChIP analysis have characterized a specific subset of potential tumor suppressor genes subject to repression via the OGT-EZH2 axis. Together these results indicate that OGT-mediated O-GlcNAcylation at S75 stabilizes EZH2 and hence facilitates the formation of H3K27me3. The study not only uncovers a functional posttranslational modification of EZH2 but also reveals a unique epigenetic role of OGT in regulating histone methylation.

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Section: Discussionsupporting

confidence: 86%

“…Sxc/Ogt, the Drosophila homolog of mammalian OGT, was identified as a polycomb group (PcG) protein involving in polycomb repression during larvae development (34,35). The chromosomal location of O-GlcNAc coincides with the PcG response elements in both Drosophila (34,35) and Caenorhabditis elegans (36).…”

mentioning

confidence: 99%

O-GlcNAcylation regulates EZH2 protein stability and function

Chu

Yeh

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

203

204

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“…OGT is essential for embryonic stem cell viability and somatic cell function (O'Donnell et al 2004;Shafi et al 2000). Deletion of OGT in Arabidopsis (Jacobsen et al 1996), Drosophila (Sinclair et al 2009;Gambetta et al 2009), and mice is lethal (Shafi et al 2000), and leads to dauer phenotypes in Caenorhabditis elegans (Hanover et al 2005), suggesting that O-GlcNAc is essential for cellular homeostasis.…”

Section: O-glcnac Transferasementioning

confidence: 99%

Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis

Groves

Lee

Yildirir

et al. 2013

Cell Stress and Chaperones

120

112

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O-linked N-acetyl-β-D-glucosamine (O-GlcNAc) is a ubiquitous and dynamic post-translational modification known to modify over 3,000 nuclear, cytoplasmic, and mitochondrial eukaryotic proteins. Addition of O-GlcNAc to proteins is catalyzed by the O-GlcNAc transferase and is removed by a neutral-N-acetyl-β-glucosaminidase (OGlcNAcase). O-GlcNAc is thought to regulate proteins in a manner analogous to protein phosphorylation, and the cycling of this carbohydrate modification regulates many cellular functions such as the cellular stress response. Diverse forms of cellular stress and tissue injury result in enhanced O-GlcNAc modification, or O-GlcNAcylation, of numerous intracellular proteins. Stress-induced OGlcNAcylation appears to promote cell/tissue survival by regulating a multitude of biological processes including: the phosphoinositide 3-kinase/Akt pathway, heat shock protein expression, calcium homeostasis, levels of reactive oxygen species, ER stress, protein stability, mitochondrial dynamics, and inflammation. Here, we will discuss the regulation of these processes by O-GlcNAc and the impact of such regulation on survival in models of ischemia reperfusion injury and trauma hemorrhage. We will also discuss the misregulation of O-GlcNAc in diseases commonly associated with the stress response, namely Alzheimer's and Parkinson's diseases. Finally, we will highlight recent advancements in the tools and technologies used to study the O-GlcNAc modification.

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“…Previous studies have hinted at a role for O-GlcNAc in transcriptional repression (29,41,42). Two recent papers have demonstrated that Drosophila ogt is allelic with super sex combs (sxc), a gene involved in repression of homeotic genes (13,14). Flies deficient in catalytically Fig.…”

Section: Disruption Of O-glcnac Cycling Affects the Aging Pathway Andmentioning

confidence: 99%

“…active Ogt develop through all larval stages, but die as pharate adults that have a variety of homeotic transformations (13,14,43). Polyhomeotic (Ph), a Polycomb group (PcG) protein, was shown to be OGlcNAc modified and was suggested to be the mediator of OGTdependent repression.…”

Section: Disruption Of O-glcnac Cycling Affects the Aging Pathway Andmentioning

confidence: 99%

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

Love

Ghosh

Mondoux

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

135

164

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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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Drosophila O -GlcNAc transferase (OGT) is encoded by the Polycomb group (PcG) gene, super sex combs ( sxc )

Cited by 214 publications

References 41 publications

O-GlcNAcylation regulates EZH2 protein stability and function

O-GlcNAcylation regulates EZH2 protein stability and function

Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis

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

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