MUC1-C IS ESSENTIAL FOR LATENT EPSTEIN-BARR VIRUS ASSOCIATED GASTRIC CANCER PATHOGENESIS
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE270984 | GEO | 2024/06/28
REPOSITORIES: GEO
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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:Epstein-Barr virus (EBV) establishes lifelong asymptomatic infection by replication of its chromatinized episomes with the host genome. EBV exhibits different latency-associated transcriptional repertoires, each with distinct three-dimensional structures. CTCF, Cohesin and PARP1 are involved in maintaining viral latency and establishing episome architecture. Epstein-Barr virus-associated gastric cancer (EBVaGC) represents 1.3% to 30.9% of all gastric cancers globally. EBV-positive gastric cancers exhibit an intermediate viral transcription profile known as "Latency II", expressing specific viral genes and noncoding RNAs. In this study, we investigated the impact of PARP1 inhibition on CTCF/Cohesin binding in Type II latency. We observed destabilization of the binding of both factors, leading to a disrupted three-dimensional architecture of the episomes and an altered viral gene expression. Despite sharing the same CTCF binding profile, Type I, II, and III latencies exhibit different 3D structures that correlate with variations in viral gene expression. Additionally, our analysis of H3K27ac-enriched interactions revealed differences between Type II latency episomes and a link to cellular transformation through docking of the EBV genome at specific sites of the Human genome, thus promoting oncogene expression. Overall, this work provides insights into the role of PARP1 in maintaining active latency and novel mechanisms of EBV-induced cellular transformation.
2023-10-11 | GSE239994 | GEO
Project description:Epstein-Barr virus (EBV) establishes lifelong asymptomatic infection by replication of its chromatinized episomes with the host genome. EBV exhibits different latency-associated transcriptional repertoires, each with distinct three-dimensional structures. CTCF, Cohesin and PARP1 are involved in maintaining viral latency and establishing episome architecture. Epstein-Barr virus-associated gastric cancer (EBVaGC) represents 1.3% to 30.9% of all gastric cancers globally. EBV-positive gastric cancers exhibit an intermediate viral transcription profile known as "Latency II", expressing specific viral genes and noncoding RNAs. In this study, we investigated the impact of PARP1 inhibition on CTCF/Cohesin binding in Type II latency. We observed destabilization of the binding of both factors, leading to a disrupted three-dimensional architecture of the episomes and an altered viral gene expression. Despite sharing the same CTCF binding profile, Type I, II, and III latencies exhibit different 3D structures that correlate with variations in viral gene expression. Additionally, our analysis of H3K27ac-enriched interactions revealed differences between Type II latency episomes and a link to cellular transformation through docking of the EBV genome at specific sites of the Human genome, thus promoting oncogene expression. Overall, this work provides insights into the role of PARP1 in maintaining active latency and novel mechanisms of EBV-induced cellular transformation.
2023-10-11 | GSE239989 | GEO
Project description:Epstein-Barr virus (EBV) establishes lifelong asymptomatic infection by replication of its chromatinized episomes with the host genome. EBV exhibits different latency-associated transcriptional repertoires, each with distinct three-dimensional structures. CTCF, Cohesin and PARP1 are involved in maintaining viral latency and establishing episome architecture. Epstein-Barr virus-associated gastric cancer (EBVaGC) represents 1.3% to 30.9% of all gastric cancers globally. EBV-positive gastric cancers exhibit an intermediate viral transcription profile known as "Latency II", expressing specific viral genes and noncoding RNAs. In this study, we investigated the impact of PARP1 inhibition on CTCF/Cohesin binding in Type II latency. We observed destabilization of the binding of both factors, leading to a disrupted three-dimensional architecture of the episomes and an altered viral gene expression. Despite sharing the same CTCF binding profile, Type I, II, and III latencies exhibit different 3D structures that correlate with variations in viral gene expression. Additionally, our analysis of H3K27ac-enriched interactions revealed differences between Type II latency episomes and a link to cellular transformation through docking of the EBV genome at specific sites of the Human genome, thus promoting oncogene expression. Overall, this work provides insights into the role of PARP1 in maintaining active latency and novel mechanisms of EBV-induced cellular transformation.
2023-10-11 | GSE239987 | GEO
Project description:Epstein-Barr virus (EBV) establishes lifelong asymptomatic infection by replication of its chromatinized episomes with the host genome. EBV exhibits different latency-associated transcriptional repertoires, each with distinct three-dimensional structures. CTCF, Cohesin and PARP1 are involved in maintaining viral latency and establishing episome architecture. Epstein-Barr virus-associated gastric cancer (EBVaGC) represents 1.3% to 30.9% of all gastric cancers globally. EBV-positive gastric cancers exhibit an intermediate viral transcription profile known as "Latency II", expressing specific viral genes and noncoding RNAs. In this study, we investigated the impact of PARP1 inhibition on CTCF/Cohesin binding in Type II latency. We observed destabilization of the binding of both factors, leading to a disrupted three-dimensional architecture of the episomes and an altered viral gene expression. Despite sharing the same CTCF binding profile, Type I, II, and III latencies exhibit different 3D structures that correlate with variations in viral gene expression. Additionally, our analysis of H3K27ac-enriched interactions revealed differences between Type II latency episomes and a link to cellular transformation through docking of the EBV genome at specific sites of the Human genome, thus promoting oncogene expression. Overall, this work provides insights into the role of PARP1 in maintaining active latency and novel mechanisms of EBV-induced cellular transformation.
2023-10-11 | GSE239992 | GEO
Project description:The Epstein-Barr virus (EBV) is associated with lymphoid and epithelial cancers. Initial EBV infection alters lymphocyte gene expression, inducing cellular proliferation and differentiation as the virus transitions through consecutive latency transcription programs. Cellular microRNAs (miRNAs) are important regulators of signaling pathways and are implicated in carcinogenesis. The extent to which EBV exploits cellular miRNAs is unknown. Using micro-array analysis and quantitative PCR, we demonstrate differential expression of cellular miRNAs in type III versus type I EBV latency including elevated expression of miR-21, miR-23a, miR-24, miR-27a, miR-34a, miR-146a and b, and miR-155. In contrast, miR-28 expression was found to be lower in type III latency. The EBV-mediated regulation of cellular miRNAs may contribute to EBV signaling and associated cancers. There were two major objectives for this study. The first objective was to determine whether EBV infected cells exhibiting type I latency influence cellular microRNA expression. For this study, four EBV negative derivatives of the type I latency cell line, Mutu I, were derived by retroviral infection with a dominant negative from of the EBV episomal replication factor, EBNA1. RNA from these four clones were compared to parental EBV positive Mutu I cells. Four dual labeling experiments were carried out for this comparison with dye reversal for every second pair of RNAs. The second objective was to determine whether EBV type III latency cells exhibit altered cellular microRNA gene expression compared to type I latency cells or EBV negative B cells. Four dual labeling experiments were carried out for this analysis with dye reversal for every second pair of RNAs.
2010-05-19 | E-GEOD-13056 | biostudies-arrayexpress
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
2015-12-16 | E-GEOD-73887 | biostudies-arrayexpress
Project description:Epstein-Barr virus (EBV) is a ubiquitous gammaherpes virus that establishes a life-long latency in over 90% of the world's population. Epstein Barr Nuclear Antigen 1, EBNA1, is the only viral protein consistently detected in all viral latency programs, as well as in all forms of EBV-associated malignancies. EBNA1 plays critical roles in the viral life cycle by fostering the replication and maintenance of the extrachromosomal viral genome as well as enhancing transcription from multiple viral promoters. Using chromatin immunoprecipitation and human promoter microarrays (an analysis termed ChIP-chip) we found that EBNA1 binds site specifically within multiple human promoters. To determine whether EBNA1’s binding to these promoters perturbed gene expression, we measured the levels of cellular mRNAs by microarrays when EBNA1 was inhibited by a dominant negative derivative of EBNA1 (DomNeg1). Keywords: viral regulation of cellular genes
2009-01-01 | GSE13315 | GEO
Project description:The Epstein-Barr virus (EBV) switches between latent and lytic phases in hosts that are important in developing related diseases. However, the underlying mechanism of how the viral latent-lytic switch is controlled and how EBV itself mediates this regulation remains largely unknown. This study identified the upregulated histone acetyl reader bromodomain-containing protein 7 (BRD7) during EBV latent infection. Based on the ChIP-sequencing of endogenous BRD7 in Burkitt lymphoma cells, we found that EBV drove BRD7 to regulate cellular and viral genomic loci, including the transcriptional activation of c-Myc, a recently reported regulator of EBV latency. Additionally, EBV-mediated BRD7 signals enriched around the FUSE site in chromosome 8, and the enhancer LOC108348026 in the lgH locus, which might activate the c-Myc alleles. Mechanically, EBV-encoded nuclear antigen 1 (EBNA1) bound and recruited BRD7 to colocalize at promotor regions of the related genes, thus serving as cofactors for the maintenance of viral latency. Moreover, the disruption of BRD7 decreased the c-Myc expression, induced the BZLF1 expression, and reactivated the lytic cycle. Our findings reveal the unique role of BRD7 hijacked by EBV in maintaining the viral latency state via chromatin remodeling. The study paved the way for understanding the new molecular mechanism of EBV-induced chromatin remodeling and latent-lytic switch regulation, providing novel therapeutic candidate targets for EBV persistent infection. With establishing persistent infection in most human hosts, EBV is usually at a latent infection state. How the viral latency is maintained in cells remains largely unknown. c-Myc was recently reported to act as a controller of the lytic switch, while whether and how EBV regulates it remains to be explored. Here, we identified that BRD7 is involved in controlling EBV latency. We found that EBV-mediated BRD7 was enriched in both the normal promoter regions and the translocation alleles of c-Myc, and the disruption of BRD7 decreased c-Myc expression to reactivate the lytic cycle. We also demonstrated that EBV-encoded EBNA1 bound to and regulated BRD7. Therefore, we reveal a novel mechanism by which EBV can regulate its infection state by hijacking host BRD7 to target c-Myc. Our findings will help future therapeutic intervention strategies of EBV infection and pathogenesis.
2022-05-14 | GSE202701 | GEO
Project description:Epstein-Barr virus (EBV) is a ubiquitous gammaherpes virus that establishes a life-long latency in over 90% of the world's population. Epstein Barr Nuclear Antigen 1, EBNA1, is the only viral protein consistently detected in all viral latency programs, as well as in all forms of EBV-associated malignancies. EBNA1 plays critical roles in the viral life cycle by fostering the replication and maintenance of the extrachromosomal viral genome as well as enhancing transcription from multiple viral promoters. Using chromatin immunoprecipitation and human promoter microarrays (an analysis termed ChIP-chip) we found that EBNA1 binds site specifically within multiple human promoters. To determine whether EBNA1â??s binding to these promoters perturbed gene expression, we measured the levels of cellular mRNAs by microarrays when EBNA1 was inhibited by a dominant negative derivative of EBNA1 (DomNeg1). Keywords: viral regulation of cellular genes We analysed mRNA expression from the EBV-positive lymphoblastoid cell line 721 transduced with either a control (empty) retroviral vector or a DomNeg1-encoding retroviral vector. For ChIP-chip, DNA from immunoprecipitated chromatin using a anti-EBNA1 antibody (IH4) along with total chromatin was hybridized to a Nimblegen human promoter arrays (CHAR0150-HP2). A single ChIP-chip experiment was performed with DNAs pooled equally from three independent ChIP experiments.
2010-05-14 | E-GEOD-13315 | biostudies-arrayexpress