β-N-Acetylglucosamine (O-GlcNAc) Is a Novel Regulator of Mitosis-specific Phosphorylations on Histone H3

Fong, Joan; Nguyen, Brenda L.; Bridger, Robert; Medrano, Estela E.; Wells, Lance; Pan, Shujuan; Sifers, Richard N.

doi:10.1074/jbc.m111.315804

Cited by 103 publications

(112 citation statements)

References 51 publications

(33 reference statements)

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“…OGT binds to the TET proteins involved in recognizing methylated CpG islands in DNA important for genomic imprinting (65)(66)(67)69). O-GlcNAc modifies histones (12,53) and participates with the polycomb and trithorax complexes responsible for histone methylation (14,26,55,101). Most RNA pol II-dependent transcription factors are O-GlcNAcylated (21).…”

Section: Resultsmentioning

confidence: 99%

“…OGT modifies many kinases and is thought to interact with numerous kinase signaling cascades both at the level of kinase regulation and through competition for acceptor serine and threonine residues (51,52). O-GlcNAc has been shown to directly modify histones including the mitosis-specific H3 Ser-10 modification, which is conditionally phosphorylated (6,12,14,53). Other sites of O-GlcNAcylation occur on histones H2A and H2B that may be linked to histone exchange (45,53).…”

Section: O-glcnac and Epigenetic Regulation Of Transcription By The Hmentioning

confidence: 99%

“…1, UDP-GlcNAc is central both to the formation of O-GlcNAc but also to the synthesis of membrane and secretory glycoproteins that perform essential roles in extracellular signaling. The intracellular O-GlcNAc modification plays a role in signaling, leading to growth and apoptosis (7-9), metabolism (10, 11), and the cell cycle (12)(13)(14). In addition, O-GlcNAc has been implicated in translation (15), circadian rhythm (16), the establishment of molecular memory in neurons (17), and calmodulinkinase signaling (16).…”

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O-GlcNAc and the Epigenetic Regulation of Gene Expression

Lewis¹,

Hanover

2014

Journal of Biological Chemistry

126

115

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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 C-terminal 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 transgenerational epigenetic inheritance.Intermediary metabolism, the process by which nutrients are converted into cellular biomass, is an interwoven network of biochemical reactions allowing reproduction, development, and response to the environment. The intermediary metabolic network is highly conserved and includes every cellular process ranging from DNA replication to transcription and translation to enzyme regulation. Epigenetics, the study of how genes may alter phenotypes beyond their ability to genetically encode information, is ultimately linked to intermediary metabolism (1). Many enzymes that participate in epigenetic gene regulation depend upon co-substrates produced by cellular metabolism, thus providing a potential link between metabolism and gene regulation (2). Mitochondria, key players in these metabolic inter-conversions, exhibit a pattern of cytoplasmic inheritance distinct from Mendelian inheritance of genes encoded in the nucleus (3). O-GlcNAcylation is a key integrator of cellular nutritional status and occurs in the nucleus, cytoplasm, and mitochondrion. O-GlcNAc transferase (OGT) 3 utilizes UDP-GlcNAc to catalyze the addition of O-GlcNAc to target proteins. UDP-GlcNAc is the end product of the hexosamine biosynthetic pathway (HSP), a series of enzymatic reactions requiring key metabolites, including glucose, glutamine, ATP, and acetyl-CoA (4). The nutrient-derived precursors render the synthesis of UDP-GlcNAc and subsequent O-GlcNAc addition by OGT nutrient-responsive. The O-GlcNAcase (OGA; MGEA5) removes the O-GlcNAc modification, and evidence suggests that its transcription and activity is highly regulated. Both enzymes of O-GlcNAc cycling contain domains that allow them to bind to epigenetic modifiers (5, 6). As illustrated in Fig. 1, UDP-GlcNAc is central both to the formation of O-GlcNAc but also to the synthesis of membrane and secretory glycoproteins that perform essential roles in extracellular signaling. The intracellular O-GlcNAc modification plays a role in signaling, leading to growth and apoptosis (7-9), metabolism (10, 11), and the cell cycle (12)(13)(14). In addition, O-GlcNAc has been implicated in translation (15), circadian rhythm (16), the establishment of molecular memory in neurons (17), and calmodulinkinase signaling (16). The focus of this review is the role of O-GlcNAc in transcripti...

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Section: Resultsmentioning

confidence: 99%

Section: O-glcnac and Epigenetic Regulation Of Transcription By The Hmentioning

confidence: 99%

mentioning

confidence: 99%

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O-GlcNAc and the Epigenetic Regulation of Gene Expression

Lewis¹,

Hanover

2014

Journal of Biological Chemistry

126

115

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“…First, OGT adds GlcNAc to DNA-binding transcription factors, such as p53, c-Myc, etc. (16), and to histone proteins such as histone H2A at T101, H2B at S36 and S112, H3 at S10 and T32, and H4 at S47 (17)(18)(19)(20). O-GlcNAcylation of H2B at S112 facilitates the ubiquitination of K120, leading to upregulation of transcriptional elongation (18).…”

mentioning

confidence: 99%

O-GlcNAcylation regulates EZH2 protein stability and function

Chu

Yeh

et al. 2014

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

195

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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“…Uma lista compreensiva de modificações em histonas observadas em humanos e suas principais funções é fornecida na Tabela 2 (Shiio & Eisenman, 2003;Khotapalli et al, 2005;Kouzarides, 2007;Zempleni et al, 2009;Baneerjee & Chakravarti, 2011;Messner & Hottiger, 2011;Zhang et al, 2011;Fong et al, 2012;Khare et al, 2012;Miller & Grant, 2012;Rossetto et al, 2012;Wright et al, 2012).…”

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Triagem funcional de genes envolvidos no processo de manutenção da inativação do cromossomo X em humanos

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β-N-Acetylglucosamine (O-GlcNAc) Is a Novel Regulator of Mitosis-specific Phosphorylations on Histone H3

Cited by 103 publications

References 51 publications

O-GlcNAc and the Epigenetic Regulation of Gene Expression

O-GlcNAc and the Epigenetic Regulation of Gene Expression

O-GlcNAcylation regulates EZH2 protein stability and function

Triagem funcional de genes envolvidos no processo de manutenção da inativação do cromossomo X em humanos

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