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CUT&RUN Sequencing of EZH2 binding sites in HEK293T cells expressing a Dual-specificity Aptamer that specifically increases O-GlcNAcylation on beta-catenin when O-GlcNAc transferase was inhibited

ABSTRACT: O-GlcNAc is a dynamic post-translational modification on thousands of intracellular proteins, it regulates protein functions and is involved in many metabolic diseases. Using a dual-specificity aptamer, we targeted the O-GlcNAc transferase (OGT) to endogenous β-catenin and specifically increased O-GlcNAcylation of β-catenin. We found that O-GlcNAc on β-catenin promoted its interaction with EZH2 regardless of the Wnt signaling status. To study how this interaction regulates the distribution of EZH2 on the genome, we performed Cleavage Under Targets and Release Using Nuclease (CUT&RUN) on HEK293T cells expressing individual (Ctrl.) or dual-specificity aptamers, under Wnt - and Wnt + conditions. This is a control experiment in which all samples were treated with the OGT inhibitor Ac5S.

ORGANISM(S): Homo sapiens

PROVIDER: GSE214774 | GEO | 2022/10/11

REPOSITORIES: GEO

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CUT&RUN Sequencing of EZH2 binding sites in HEK293T cells expressing a Dual-specificity Aptamer that specifically increases O-GlcNAcylation on beta-catenin

Project description:O-GlcNAc is a dynamic post-translational modification on thousands of intracellular proteins, it regulates protein functions and is involved in many metabolic diseases. Using a dual-specificity aptamer, we targeted the O-GlcNAc transferase (OGT) to endogenous β-catenin and specifically increased O-GlcNAcylation of β-catenin. We found that O-GlcNAc on β-catenin promoted its interaction with EZH2 regardless of the Wnt signaling status. To study how this interaction regulates the distribution of EZH2 on the genome, we performed Cleavage Under Targets and Release Using Nuclease (CUT&RUN) on HEK293T cells expressing individual (Ctrl.) or dual-specificity aptamers. Under Wnt - and Wnt + conditions, the dual-specificity aptamer increased the binding of EZH2 on 923 and 3473 genomic sites, respectively. These two sets of differential binding sites showed little overlap.

2022-11-30 | GSE190172 | GEO

CUT&RUN Sequencing of EZH2 binding sites in HEK293T cells expressing a Dual-specificity Aptamer that specifically increases O-GlcNAcylation on beta-catenin, when beta-catein was knocked-down

Project description:O-GlcNAc is a dynamic post-translational modification on thousands of intracellular proteins, it regulates protein functions and is involved in many metabolic diseases. Using a dual-specificity aptamer, we targeted the O-GlcNAc transferase (OGT) to endogenous β-catenin and specifically increased O-GlcNAcylation of β-catenin. We found that O-GlcNAc on β-catenin promoted its interaction with EZH2 regardless of the Wnt signaling status. To study how this interaction regulates the distribution of EZH2 on the genome, we performed Cleavage Under Targets and Release Using Nuclease (CUT&RUN) on HEK293T cells expressing individual (Ctrl.) or dual-specificity aptamers, under Wnt - and Wnt + conditions. This is a control experiment in beta-catenin knockdown cells.

2022-10-11 | GSE214775 | GEO

RNA Sequencing of HEK293T cells expressing a Dual-specificity Aptamer that specifically increases O-GlcNAcylation on beta-catenin when EZH2 was knocked-down

Project description:O-GlcNAc is a dynamic post-translational modification on thousands of intracellular proteins, it regulates protein functions and is involved in many metabolic diseases. Using a dual-specificity aptamer, we targeted the O-GlcNAc transferase (OGT) to endogenous β-catenin and specifically increased O-GlcNAcylation of β-catenin. To study how O-GlcNAcylation of β-catenin regulates the transcriptome, we performed RNA sequencing on HEK293T cells expressing individual (Ctrl.) or dual-specificity aptamers. This dataset is from the control experiment in which EZH2 was knocked-down with a shRNA in all samples.

2022-10-11 | GSE214777 | GEO

RNA Sequencing of HEK293T cells expressing a Dual-specificity Aptamer that specifically increases O-GlcNAcylation on beta-catenin

Project description:O-GlcNAc is a dynamic post-translational modification on thousands of intracellular proteins, it regulates protein functions and is involved in many metabolic diseases. Using a dual-specificity aptamer, we targeted the O-GlcNAc transferase (OGT) to endogenous β-catenin and specifically increased O-GlcNAcylation of β-catenin. To study how O-GlcNAcylation of β-catenin regulates the transcriptome, we performed RNA sequencing on HEK293T cells expressing individual (Ctrl.) or dual-specificity aptamers. We found that O-GlcNAcylation of β-catenin shifts the transcriptome in a Wnt-dependent manner: it repressed the expression of about 100 genes in the absence of Wnt, while it activated the expression of these genes when Wnt signaling was turned on.

2022-11-01 | GSE189378 | GEO

RNA Sequencing of HEK293T cells expressing a Dual-specificity Aptamer that specifically increases O-GlcNAcylation on beta-catenin when O-GlcNAc transferase was inhibited

Project description:O-GlcNAc is a dynamic post-translational modification on thousands of intracellular proteins, it regulates protein functions and is involved in many metabolic diseases. Using a dual-specificity aptamer, we targeted the O-GlcNAc transferase (OGT) to endogenous β-catenin and specifically increased O-GlcNAcylation of β-catenin. To study how O-GlcNAcylation of β-catenin regulates the transcriptome, we performed RNA sequencing on HEK293T cells expressing individual (Ctrl.) or dual-specificity aptamers. We found that O-GlcNAcylation of β-catenin shifts the transcriptome in a Wnt-dependent manner: it repressed the expression of about 100 genes in the absence of Wnt, while it activated the expression of these genes when Wnt signaling was turned on. This dataset is from the control experiment in which all samples were treated with the OGT inhibitor Ac5S.

2022-11-01 | GSE189622 | GEO

RNA-sequencing and ChIP-sequencing in murine mesenchymal stem cells treated with Ezh2 inhibitor GSK126 or β-catenin siRNA

Project description:During mesenchymal stem cell (MSC) differentiation, both Wnt signaling and the development of a rigid cytoskeleton promote commitment to the osteoblastic over adipogenic lineage. β-catenin is thought to play a critical role in Wnt effects. We show that β-catenin was additive with cytoskeletal signals to prevent adipogenesis, and β-catenin knockdown promoted adipogenesis even when the actin cytoskeleton was depolymerized. β-catenin also prevented osteoblast commitment in a cytoskeletal-independent manner, with β-catenin knockdown enhancing lineage commitment. Chip-seq showed that β-catenin associated with the promoter of EZH2, a key component of the PRC2 complex that governs genome methylation. Knocking down β-catenin lowered EZH2 levels and H3K27me3 at osteogenic loci. Further, when EZH2 was inhibited, β-catenin ’s anti-differentiation effects were lost. These results indicate that regulating EZH2 activity is key to β-catenin effects on MSC to preserve MSC multipotentiality.

2019-10-17 | GSE138980 | GEO

RNA-seq analysis of WT and βOGT KO female islets

Project description:We report our results from two runs of RNA-seq analysis on islets isolated from female C57Bl/6J mice with a constitutive deletion of O-GlcNAc Transferase (OGT) specifically in pancreatic β-cells (Rip-cre; Ogt f/f) and controls (Ogt f/f or Ogt f/+)

2020-04-10 | GSE144760 | GEO

Conserved nutrient sensor O-GlcNAc transferase is integral to the C. elegans pathogen-specific immune response

Project description:Discriminating pathogenic bacteria from energy-harvesting commensals is key to host immunity. Using mutants defective in the enzymes of O-linked N-acetylglucosamine (O-GlcNAc) cycling, we examined the role of this nutrient-sensing pathway in the Caenorhabidits elegans innate immune response. Using whole genome transcriptional profiling, O-GlcNAc cycling mutants exhibited deregulation of unique stress- and immune-responsive genes as well as genes shared with the p38 MAPK/PMK-1 pathway. Moreover, genetic analysis showed that deletion of O-GlcNAc transferase (ogt-1) yielded animals hypersensitive to the human pathogen S. aureus but not to P. aeruginosa. Genetic interaction studies further revealed that nutrient-responsive OGT-1 acts through the conserved ß-catenin (BAR-1) pathway and in concert with p38 MAPK/PMK-1 to modulate the immune response to S. aureus. The participation of the nutrient sensor O-GlcNAc transferase in an immunity module conserved from C. elegans to humans reveals an unexplored nexus between nutrient availability and a pathogen-specific immune response. In C. elegans, three mutant strains(genotypes used: N2 (wild-type), ogt-1 (ok1474), oga-1 (ok1207), and pmk-1 (km25)) were treated with the human pathogen S. aureus (SA) or P. aeruginosa(PA) and OP50 (E. coli control) with three biological replications.

2015-05-01 | E-GEOD-53732 | biostudies-arrayexpress

Genome-wide changes in OGT-deficient mouse liver tissue

Project description:Over a billion people suffer from chronic liver diseases worldwide, which often leads to fibrosis and then cirrhosis. Treatments for fibrosis remain experimental, in part because no unifying mechanism has been identified that initiates liver fibrosis. O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) plays a pro-survival role under stress in many tissues. Here we report that OGT protects against hepatocyte necroptosis and initiation of liver fibrosis. Decreased O-GlcNAc levels were seen in patients with alcoholic liver cirrhosis and in mice with ethanol-induced liver injury. Liver-specific O-GlcNAc transferase (OGT) knockout (OGT-LKO) mice progressed to liver fibrosis at 10 weeks of age. OGT-deficient hepatocytes underwent necroptosis. These findings identify OGT as a key suppressor of hepatocyte necroptosis and OGT-LKO mice may serve as an effective spontaneous genetic model of liver fibrosis.

2019-11-04 | GSE134993 | GEO

CCN6/WISP3 suppresses metaplastic breast carcinoma by antagonizing a WNT/b-catenin/EZH2 cascade [ChIP-seq]

Project description:Metaplastic breast carcinomas (mBrCAs) are a highly aggressive subtype of triple negative breast cancer (TNBC) with histological evidence of epithelial to mesenchymal transition (EMT) and aberrant differentiation, including varied non-glandular features. CCN6/WISP3 tumor suppressor gene inactivation and b-catenin-dependent Wnt pathway activation are often seen in mBrCAs. We have reported MMTV-Cre;Ccn6fl/fl (Ccn6-KO) mice develop spindle mBrCAs with EMT and elevated expression of the Wnt/b-catenin pathway genes HMGA2 and IGF2BP2. The mechanisms by which the secreted CCN6 protein exerts tumor suppressor functions in breast tissues are uncertain. Here, we show recombinant CCN6 protein interacts with Wnt receptor FZD8 and co-receptor LRP6 on mBrCA cells to antagonize Wnt ligand-mediated activation of b-catenin/T-cell-factor (TCF) transcription. We identify the gene for histone methyltransferase EZH2, the catalytic component of polycomb repressive complex 2, as a β-catenin/TCF transcriptional target in Ccn6-KO mBrCA cells. Inhibition of Wnt/β-catenin/TCF function in Ccn6-KO mBrCA cells led to reduced EZH2 levels and decreased histone H3 lysine 27 trimethylation, resulting in deregulation of specific gene targets. Pharmacological inhibition of EZH2 reduced growth and metastasis of Ccn6-KO mBrCA mammary tumors and induced an epithelial phenotype in vivo. In human breast cancer specimens, low CCN6 is significantly associated with activated β-catenin and high EZH2 in spindle mBrCAs compared to other subtypes. Collectively, our findings establish a novel tumor suppressor mechanism for CCN6 as a key negative regulator of a b-catenin/TCF-EZH2 axis and highlight how CCN6 restoration or b-catenin or EZH2 inhibition could have therapeutic relevance for patients with spindle mBrCAs.

2024-07-10 | GSE250574 | GEO

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