Essential Role of the Glycosyltransferase Sxc/Ogt in Polycomb Repression

Gambetta, Maria Cristina; Oktaba, Katarzyna; Müller, Jürg

doi:10.1126/science.1169727

Cited by 288 publications

(370 citation statements)

References 21 publications

Supporting

Mentioning

355

Contrasting

Order By: Relevance

“…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: 80%

“…Three of the PRC1 components, Ph, Pc, and Ring, are likely Sxc/Ogt substrates in Drosophila (34). However, these observations have not been confirmed by mass spectrometry analysis, and no function has been reported with regard to the O-GlcNAcylation of these proteins (34). In the present study, using an unbiased small-scale screening, we independently demonstrate that OGT depletion leads to the downregulation of H3K27me3.…”

Section: Significancementioning

confidence: 47%

“…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%

See 2 more Smart Citations

O-GlcNAcylation regulates EZH2 protein stability and function

Chu

Yeh

et al. 2014

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

203

204

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 80%

Section: Significancementioning

confidence: 47%

See 1 more Smart Citation

O-GlcNAcylation regulates EZH2 protein stability and function

Chu

Yeh

et al. 2014

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

203

204

View full text Add to dashboard Cite

show abstract

“…2A). GRMZM2G477503 is annotated as a glycosyl transferase, a protein that can potentially be involved in polycomb repression (30). Results of 5′ and 3′ RACE showed that ZmMNC-18 is transcribed in the same direction as GRMZM2G477503 and has a poly(A) tail (Fig.…”

Section: Resultsmentioning

confidence: 99%

Extensive, clustered parental imprinting of protein-coding and noncoding RNAs in developing maize endosperm

Zhang

Zhao

Xie

et al. 2011

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

169

228

View full text Add to dashboard Cite

Although genetic imprinting was discovered in maize 40 years ago, its exact extent in the triploid endosperm remains unknown. Here, we have analyzed global patterns of allelic gene expression in developing maize endosperms from reciprocal crosses between inbreds B73 and Mo17. We have defined an imprinted gene as one in which the relative expression of the maternal and paternal alleles differ at least fivefold in both hybrids of the reciprocal crosses. We found that at least 179 genes (1.6% of protein-coding genes) expressed in the endosperm are imprinted, with 68 of them showing maternal preferential expression and 111 paternal preferential expression. Additionally, 38 long noncoding RNAs were imprinted. The latter are transcribed in either sense or antisense orientation from intronic regions of normal protein-coding genes or from intergenic regions. Imprinted genes show a clear pattern of clustering around the genome, with a number of imprinted genes being adjacent to each other. Analysis of allele-specific methylation patterns of imprinted loci in the hybrid endosperm identified 21 differentially methylated regions (DMRs) of several hundred base pairs in length, corresponding to both imprinted genes and noncoding transcripts. All DMRs identified are uniformly hypomethylated in maternal alleles and hypermethylated in paternal alleles, regardless of the imprinting direction of their corresponding loci. Our study indicates highly extensive and complex regulation of genetic imprinting in maize endosperm, a mechanism that can potentially function in the balancing of the gene dosage of this triploid tissue.

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

Essential Role of the Glycosyltransferase Sxc/Ogt in Polycomb Repression

Cited by 288 publications

References 21 publications

O-GlcNAcylation regulates EZH2 protein stability and function

O-GlcNAcylation regulates EZH2 protein stability and function

Extensive, clustered parental imprinting of protein-coding and noncoding RNAs in developing maize endosperm

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

Contact Info

Product

Resources

About