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Chromatin-associated OGT promotes hepatocellular carcinoma malignancy via activating ZNF263 [ChIP-seq]

ABSTRACT: The reversible and dynamic O-GlcNAcylation regulates vast networks of highly coordinated cellular and nuclear processes. Despite the dysregulation of the sole enzyme O-GlcNAc transferase (OGT), is showed to associated with the progression of hepatocellular carcinoma (HCC), the mechanisms by which OGT controls the cis-regulatory elements in the genome and achieves transcriptional functions remain unclear. Here, we demonstrate that the elevated OGT increases HCC proliferation and metastasis by orchestrating the transcription of numerous malignant regulators in vitro and in vivo. Diverse transcriptional regulators are recruited by OGT in HCC cells with progressive malignancy, which shapes the genome-wide OGT chromatin cis-elements occupation. Further, an unrecognized cooperation between ZNF263 and OGT is crucial for activating downstream transcriptomics. We reveal that the O-GlcNAcylation site Ser662 is responsible for ZNF263 chromatin association at candidate gene promoters and OGT facilitated HCC the malignant phenotypes. Our data establish the importance of aberrant OGT and ZNF263 O-GlcNAcylation in HCC malignant progression, and represents the pursuit of OGT as a target for HCC therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE222280 | GEO | 2023/01/09

REPOSITORIES: GEO

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Chromatin-associated OGT promotes hepatocellular carcinoma malignancy via activating ZNF263 [RNA-seq]

Project description:The reversible and dynamic O-GlcNAcylation regulates vast networks of highly coordinated cellular and nuclear processes. Despite the dysregulation of the sole enzyme O-GlcNAc transferase (OGT), is showed to associated with the progression of hepatocellular carcinoma (HCC), the mechanisms by which OGT controls the cis-regulatory elements in the genome and achieves transcriptional functions remain unclear. Here, we demonstrate that the elevated OGT increases HCC proliferation and metastasis by orchestrating the transcription of numerous malignant regulators in vitro and in vivo. Diverse transcriptional regulators are recruited by OGT in HCC cells with progressive malignancy, which shapes the genome-wide OGT chromatin cis-elements occupation. Further, an unrecognized cooperation between ZNF263 and OGT is crucial for activating downstream transcriptomics. We reveal that the O-GlcNAcylation site Ser662 is responsible for ZNF263 chromatin association at candidate gene promoters and OGT facilitated HCC the malignant phenotypes. Our data establish the importance of aberrant OGT and ZNF263 O-GlcNAcylation in HCC malignant progression, and represents the pursuit of OGT as a target for HCC therapy.

2023-01-09 | GSE222281 | GEO

OGT, H2B S112GlcNAc, TET2 ChIP-seq results

Project description:TET2 directly interacts with OGT, which is important for the chromatin association of OGT in vivo. Although this specific interaction does not regulate the enzymatic activity of TET2, it facilitates OGT-dependent histone O-GlcNAcylation. Moreover, OGT associates with TET2 at transcription starting sites (TSS). Down-regulation of TET2 reduces the amount of H2B S112 GlcNAc marks in vivo, which are associated with gene transcription regulation. We found that OGT interacts with TET2 tightly. Using ChIP-seq with specific antibodies, we tested the co-localization of TET2 and OGT in genome level.

2012-12-11 | E-GEOD-41720 | biostudies-arrayexpress

TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and SET1/COMPASS

Project description:TET proteins convert 5-methylcytosine to 5-hydroxymethylcytosine, an emerging dynamic epigenetic state of DNA that can influence transcription. Evidence has linked TET1 function to epigenetic repression complexes, yet mechanistic information, especially for the TET2 and TET3 proteins, remains limited. Here, we show a direct interaction of TET2 and TET3 with O-GlcNAc transferase (OGT). OGT does not appear to influence hmC activity, rather TET2 and TET3 promote OGT activity. TET2/3-OGT co-localize on chromatin at active promoters enriched for H3K4me3 and reduction of either TET2/3 or OGT activity results in a direct decrease in H3K4me3 and concomitant decreased transcription. Further, we show that Host Cell Factor 1 (HCF1), a component of the H3K4 methyltransferase SET1/COMPASS complex, is a specific GlcNAcylation target of TET2/3-OGT, and modification of HCF1 is important for the integrity of SET1/COMPASS. Additionally, we find both TET proteins and OGT activity promote binding of the SET1/COMPASS H3K4 methyltransferase, SETD1A, to chromatin. Finally, studies in Tet2 knockout mouse bone marrow tissue extend and support the data as decreases are observed of global GlcNAcylation and also of H3K4me3, notably at several key regulators of haematopoiesis. Together, our results unveil a step-wise model, involving TET-OGT interactions, promotion of GlcNAcylation, and influence on H3K4me3 via SET1/COMPASS, highlighting a novel means by which TETs may induce transcriptional activation. ChIP-Seq experiments were performed on Illumina HiScanSQ sequencer in wild-type HEK293T cells for H3K4me3 histone marks, O-GlcNAc and HCF1, for HT-TET2, HT-TET3 and HT-OGT in HEK293T cells overexpressing those three fusion proteins and in TET2 Kd HEK293T cells for H3K4me3 histone marks. ChIP-Seqs were also performed in mouse bone marrow tissues for H3K4me3 histone marks, O-GlcNAc, endogenous Tet2 and in Tet2 Ko bone marrow tissues for H3K4me3 histone marks.

2013-02-07 | E-GEOD-36620 | biostudies-arrayexpress

Dot1L recruits OGT target chromatin to regulate histones O-GlcNAcylation

Project description:OGT (O-GlcNAc transferase) is the distinctive enzyme responsible for catalyzing O-GlcNAc to the serine or threonine residues of thousands of cytoplasm and nuclear proteins that are involved in DNA damage, RNA splicing, and transcription preinitiation and initiation complex assembly. However, the molecular mechanism by OGT regulating gene transcription remains elusive. Using proximity labeling based mass spectrometry, we searched for functional partners of OGT and found that Dot1L, the conserved and unique histone methyltransferase mediated histone H3 lys79 methylation required for gene transcription, DNA damage repair, cell proliferation, and embryo development, interacts with OGT. Although this specific interaction does not regulate the enzymatic activity of Dot1L, it facilitates OGT-dependent histones O-GlcNAcylation. Moreover, OGT associates with Dot1L at transcription start sites, and depleting Dot1L decreased OGT associated with chromatin globally. Notably, downregulation of Dot1L reduces the levels of histone H2B S112 O-GlcNAcylation and histone H2B K120 ubiquitination in vivo, which are associated with gene transcription regulation. Taken together, these results reveal a Dot1L-dependent O-GlcNAcylation of chromatin.

2022-04-06 | GSE200059 | GEO

OGT, H2B S112GlcNAc, TET2 ChIP-seq results

2012-12-11 | GSE41720 | GEO

TET2 and TET3 regulate GlcNAcylation and H3K4 methylation through OGT and SET1/COMPASS

2013-02-07 | GSE36620 | GEO

Effect of O-GlcNAc Transferase (OGT) siRNA in trophoblastic BeWo cells

Project description:Every year, about 18 million babies are born from mothers with gestational diabetes mellitus (GDM). While diabetic symptoms usually resolve after delivery, lasting complications can occur for both mother and child, including fetal overgrowth, type 2 diabetes (T2D), cardiovascular diseases, and obesity. The rapid progression of GDM is unique to pregnancies, and likely arises from placental dysfunction. Indeed, stress, nutrition and fetal gender are thought to trigger changes in placental endocrine function, including metabolic hormones and inflammatory cytokines, potentially causing GDM. Nutrient-sensing O-GlcNAcylation and its enzyme O-GlcNAc Transferase (OGT, X-linked) has been previously identified as a placental biomarker of maternal stress particularly deleterious for male offspring. Thus, we wondered whether O-GlcNAcylation participate in GDM development in a sex-dependent manner. After demonstrating that OGT is largely downregulated in male GDM compared to healthy placentas, we knocked down OGT in male trophoblastic cells. We observed changes in placental hormones, cytokines and nutrient-sensing pathways, correlating with previously demonstrated disruption in GDM placentas. Altogether, this study demonstrates that OGT and O-GlcNAcylation are partly responsible for changes observed in GDM placenta and might be the cause of sexual dimorphism observed in this pathology.

2022-04-21 | GSE200983 | GEO

Chromatin-associated OGT promotes hepatocellular carcinoma malignancy via activating ZNF263

Project description:OGT, the only facilitator which attaches the monosaccharide to many oncogenic factors or tumor suppressors, has been suggested to play an influential role in tumorigenesis and metastasis of HCC. OGT interactome analyses indicates that disordered OGT may serve as a hub protein to activate the building of aberrant transcriptional regulatory complexes, supporting that this unique enzyme is an essential regulator in tumor progression. However, the function and related mechanisms by which OGT triggers HCC malignancy are still largely unknown

2023-01-12 | PXD039365 | iProX

Genome-wide changes in OGT-depleted mouse adipose tissue

Project description:Appetite control is key to combat obesity in an over-nutritious environment. Whether and how over-nutrition induces hyperphagia and obesity through the adipose-to-brain axis is unclear. O-linked beta-D-N-acetylglucosamine (O-GlcNAc) transferase (OGT) couples nutrient cues to O-GlcNAcylation of intracellular proteins at serine/threonine residues. Here we show that adipocyte OGT is essential for high fat diet-induced hyperphagia, but is dispensable for baseline food intake. Adipocyte OGT stimulates hyperphagia by transcriptional activation of de novo lipid desaturation and accumulation of anandamide (AEA), an endogenous appetite-inducing cannabinoid (CB). Pharmacological manipulation of peripheral CB1 signaling regulates hyperphagia in an adipocyte OGT-dependent manner. These findings define adipocyte OGT as a fat sensor that regulates peripheral lipid signals, and uncover an unexpected adipose-to-brain axis that induces hyperphagia and obesity.

2018-09-12 | GSE111735 | GEO

Ogt Controls Adult Neurogenesis through Modulating Notch Signaling Activity in Mice

Project description:Ogt catalyzed O-linked N-acetylglucosamine (O-GlcNAcylation, O-GlcNAc) plays an important function in diverse biological processes and diseases. However, the roles of Ogt in regulating neurogenesis remain largely unknown. Here, we show that Ogt deficiency or depletion in adult neural stem cells (aNSCs) leads to the diminishment of aNSCs pool and the aberrant neurogenesis, and consequently impairs cognitive function of adult mice. RNA sequencing reveals that Ogt deficiency alters the transcription of genes relating to cell cycle, neurogenesis, and neuronal development. Mechanistic studies show that Ogt directly interacts with Notch1 and catalyzes the O-GlcNAc modification of Notch TM/ICD fragment. The decreased O-GlcNAc modification of TM/ICD increases the binding of E3 ubiquitin ligase Itch to TM/ICD and promotes its degradation. Itch knockdown rescues neurogenic defects in Ogt-deficient mice. OGT also regulates human cortical neurogenesis in forebrain organoids derived from induced pluripotent stem cells. Our findings reveal the essential roles and mechanisms of Ogt and O-GlcNAc modification in regulating mammalian neurogenesis and cognition.

2020-12-15 | GSE163141 | GEO

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