USP7 inhibitors disrupt EBNA1 interactome and EBV tumorigenesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1200707 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31780829_1.fastq.gz | Fastqsanger.gz | |||
| SRR31780829_2.fastq.gz | Fastqsanger.gz | |||
| SRR31780830_1.fastq.gz | Fastqsanger.gz | |||
| SRR31780830_2.fastq.gz | Fastqsanger.gz | |||
| SRR31780831_1.fastq.gz | Fastqsanger.gz |
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Project description:Epstein-Barr virus (EBV) is a ubiquitous human ɣ-herpesvirus implicated in various malignancies, including Burkitt’s lymphoma and gastric carcinomas. In most EBV-associated cancers, the viral genome is maintained as an extrachromosomal episome by the EBV nuclear antigen-1 (EBNA1). EBNA1 is considered to be a highly stable protein that interacts with the ubiquitin-specific protease 7 (USP7), but the precise role of USP7 in controlling EBNA1 stability and function is not fully understood. Here, we show that pharmacological inhibitors and small interfering RNA (siRNA) targeting USP7 reduce EBNA1 protein levels. The USP7 inhibitor GNE6776 altered EBNA1 protein interactions, including disrupting its ability to bind to USP7. GNE6776 also inhibited EBNA1 binding to EBV oriP DNA and reduced viral episome copy number. GNE6776 selectively inhibited EBV+ gastric and lymphoid cell proliferation in cell culture and slowed EBV+ tumor growth in mouse xenograft models. Transcriptomic studies revealed that USP7 inhibition differentially affected EBV+ cancer cells compared to EBV- cells with a significant effect on chromosome segregation and mitotic cell division pathways. Our findings indicate that USP7 inhibition perturbs EBNA1 stability and function and can be exploited to target EBV+ cancer cells selectively.
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Project description:RIP-Seq of the viral protein EBNA1-HA-FLAG from EBV in HEK293T cells
2019-03-01 | GSE107808 | GEO
Project description:EBNA1 is the EBV-encoded nuclear antigen required for viral episome maintenance during latency. EBNA1 is a sequence specific DNA binding protein with high affinity binding sites for the viral genome, especially OriP. EBNA1 can also bind sequence specifically to a large number of sites in the host cellular genome, but the function of these binding sites has remained elusive. EBNA1 is also known to provide a host cell survival function, but the molecular mechanisms accounting for this function are not completely understood. Here, we show by integrating ChIP-Seq and RNA-Seq with experimental validation that MEF2B, IL6R, and EBF1 are high confidence target genes of EBNA1 that are essential for viability of B-lymphocytes latently infected with EBV. We show that EBNA1 binds to ~1000 sites with many, but not all, universally bound in different cell types, including Burkitt lymphoma (BL) and nasopharyngeal carcinoma (NPC). We find that a large subset of EBNA1 binding sites are located proximal to transcription start sites and correlate genome-wide with transcription activity. EBNA1 bound to genes of high significance for B-cell growth and function, including MEF2B, IL6R, EBF1, RNF145, POU2F1, KDM4C, FGR, EGFR, LAIR, CDC7, CD44, and IL17A. EBNA1 depletion from latently infected LCLs results in the loss of cell proliferation, and the loss of gene expression for some EBNA1-bound genes, including MEF2B, EBF1, and IL6R. Depletion of MEF2B, EBF1, or IL6R partially phenocopies EBNA1-depletion by decreasing EBV-positive cell growth and viability. These findings indicate that EBNA1 binds to a large cohort of cellular genes important for cell viability, and implicates EBNA1 as a master coordinator of host cell gene expression important for enhanced survival of latently infected cells. Examination of EBNA1 binding in Raji, MutuI, LCL and C666-1 cells and EBNA1 knockdown effect on mRNA gene expression in LCL
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Project description:Epstein-Barr virus (EBV) genomes persist in latently infected cells as extrachromosomal plasmids that attach to host chromosomes through the tethering functions of EBNA1, a viral encoded sequence-specific DNA binding protein. Here we employed circular chromosome conformation capture (4C) analysis to identify genomewide associations between EBV episomes and host chromosomes. We found that EBV episomes in Burkitt lymphoma (BL) cells preferentially associate with EBNA1 sequence-specific DNA binding sites in the cellular genome that are also enriched for B-cell factors EBF1 and RBP-jK, the repressive histone mark H3K9me3, and surrounded by AT-rich sequence. These attachment sites corresponded to transcriptionally silenced genes with enrichment in neuronal function. Depletion of EBNA1 from EBV latently infected BL cells led to a transcriptional de-repression of these silenced genes. EBV attachment sites in lymphoblastoid cells (LCLs) showed different correlations, suggesting that latency types are functionally linked to the epigenetic environment of host chromosome attachment sites.
2019-11-14 | GSE129703 | GEO
Project description:EBNA1 is the EBV-encoded nuclear antigen required for viral episome maintenance during latency. EBNA1 is a sequence specific DNA binding protein with high affinity binding sites for the viral genome, especially OriP. EBNA1 can also bind sequence specifically to a large number of sites in the host cellular genome, but the function of these binding sites has remained elusive. EBNA1 is also known to provide a host cell survival function, but the molecular mechanisms accounting for this function are not completely understood. Here, we show by integrating ChIP-Seq and RNA-Seq with experimental validation that MEF2B, IL6R, and EBF1 are high confidence target genes of EBNA1 that are essential for viability of B-lymphocytes latently infected with EBV. We show that EBNA1 binds to ~1000 sites with many, but not all, universally bound in different cell types, including Burkitt lymphoma (BL) and nasopharyngeal carcinoma (NPC). We find that a large subset of EBNA1 binding sites are located proximal to transcription start sites and correlate genome-wide with transcription activity. EBNA1 bound to genes of high significance for B-cell growth and function, including MEF2B, IL6R, EBF1, RNF145, POU2F1, KDM4C, FGR, EGFR, LAIR, CDC7, CD44, and IL17A. EBNA1 depletion from latently infected LCLs results in the loss of cell proliferation, and the loss of gene expression for some EBNA1-bound genes, including MEF2B, EBF1, and IL6R. Depletion of MEF2B, EBF1, or IL6R partially phenocopies EBNA1-depletion by decreasing EBV-positive cell growth and viability. These findings indicate that EBNA1 binds to a large cohort of cellular genes important for cell viability, and implicates EBNA1 as a master coordinator of host cell gene expression important for enhanced survival of latently infected cells.
2015-12-16 | GSE73887 | GEO
Project description:The viral nuclear antigen 1 (EBNA1) of Epstein Barr (EBV) features two functionally redundant Arginine-Glycine (RG) repeats that contain symmetrically and asymmetrically di-methylated (SDMA/ADMA) and also mono-methylated (MMA) Arginine residues. We generated mouse monoclonal antibodies against the mono-methylated RG-repeat between aa 328-377. In addition to detect MMA-EBNA1, we aimed at the identification of cellular proteins that are bound to MMA-modified EBNA1 in EBV-positive Raji cells.
2025-03-05 | PXD051181 | Pride
Project description:Background: In several types of malignancies, especially EBV-associated nasopharyngeal carcinomas, high Galectin-9 (Gal-9) expression is indicative of an aggressive tumor phenotype. The contribution of Gal-9 to the oncogenesis of B-cell lymphomas (BCLs) has not yet been investigated. Methods: The expression of Gal-9, STING, and EBNA1 was measured by immunohistochemical (IHC) staining on tumor sections from 66 BCL patients. Artificial EBV infection of normal primary B cells in vitro was used as an experimental model. The dynamic changes of the transcriptome of EBV-infected B cells undergoing transformation were investigated by bulk RNA-sequencing and bioinformatics analysis. The oncogenic role of Gal-9 was investigated in vitro by addition of recombinant Gal-9 to EBV-infected primary B-cells, and growth assays. The underlying molecular mechanisms were investigated by immunoblotting and immunofluorescent (IF) staining, CHIP and luciferase reporter assays. Results: In clinical specimens of BCLs, Gal-9 expression was significantly associated with tumor stage, latent EBV infection and abundance of the viral latent protein EBNA1. Looking at the transcriptome changes occurring in vitro during EBV-driven B-cell transformation, we could identify a series of genes undergoing long term activation and remaining highly expressed in mature LCLs. The Gal-9 gene is one of them. Its expression is enhanced during the transformation process at the mRNA level and even more at the protein level. This up-regulation results at least in part from its transactivation by EBNA1 which can bind its promoter. Reciprocally, we find that addition of extra-cellular Gal-9 promotes B-cell transformation and establishment of the latent phase of EBV-infection. Concomitantly, extra-cellular Gal-9 blocks STING signaling and enhances STAT3 phosphorylation. Inhibition of Sting signaling or STAT3 phosphorylation blocks B-cell transformation, even in the presence of Gal-9. Conclusion: our data unveil a role of amplification and acceleration for Gal-9 in the process of EBV-driven B-cell transformation. This process might be relevant to the pathogenesis of EBV-associated BCLs.
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