Identification of Host Biomarkers of EBV Latency IIb and Latency III
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA546009 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9189580.fastq.gz | Fastqsanger.gz | |||
| SRR9189581.fastq.gz | Fastqsanger.gz | |||
| SRR9189582.fastq.gz | Fastqsanger.gz | |||
| SRR9189583.fastq.gz | Fastqsanger.gz | |||
| SRR9189574.fastq.gz | Fastqsanger.gz |
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Project description:Deciphering the molecular pathogenesis of virally induced cancers is challenging due, in part, to the heterogeneity of both viral and host gene expression. Epstein-Barr Virus (EBV) is a ubiquitous herpesvirus prevalent in B-cell lymphomas of the immune suppressed. EBV infection of primary human B cells leads to their immortalization into lymphoblastoid cell lines (LCLs) serving as a model of these lymphomas. In previous studies, our lab has described a temporal model for immortalization with an initial phase characterized by expression of the Epstein-Barr Nuclear Antigens (EBNAs), high c-Myc activity, and hyper-proliferation in the absence of the Latent Membrane Proteins (LMPs), called latency IIb. This is followed by the long-term outgrowth of LCLs expressing the EBNAs along with the LMPs, particularly the NFkB-activating LMP1, defining latency III. LCLs, however, express a broad distribution of LMP1 such that a subset of these cells expresses LMP1 at levels seen in latency IIb, making it difficult to distinguish these two latency states. In this study, we performed mRNA-Seq on early EBV-infected latency IIb cells and latency III LCLs sorted by NFkB activity. We found that latency IIb transcriptomes clustered independently from latency III independent of NFkB. We identified and validated mRNAs defining these latency states. Indeed, we were able to distinguish latency IIb cells from LCLs expressing low levels of LMP1 using multiplex RNA-FISH targeting EBV EBNA2, LMP1, and human CCR7 or MGST1. This study defines latency IIb as a bona fide latency state independent from latency III and identifies biomarkers for understanding EBV-associated tumor heterogeneity
2019-06-04 | GSE132138 | 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: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.
2008-10-07 | GSE13056 | GEO
Project description:Epstein-Barr virus (EBV) is a ubiquitous human pathogen that is etiologically linked to several cancers and has been connected to multiple sclerosis. EBV employs a series of latency programs, including latency III, latency II, and latency I, to persistently colonize the B-cell compartment. Each of these programs is associated with human malignancies. However, our understanding remains incomplete of how these distinct latency programs are epigenetically restricted. While regulation of the chromatin structure of the EBV genome by cohesin and CTCF contributes to genome regulation, the function of the cohesin release factor Wings Apart-Like Protein Homolog (WAPL) had not previously been understood. In this study, we employ RNA-seq combined with immunofluorescence analysis to determine that loss of WAPL leads to aberrant expression of the oncogenic latent membrane proteins LMP1 and LMP2A in latency I Burkitt lymphoma cells. Through a combination of Hi-C, Hi-ChIP, and ChIP-qPCR, we uncover that WAPL loss causes alterations in looping across the EBV genome and specifically induces formation of loops between the LMP promoter and the oriLyt enhancers. We propose that EBV coopts WAPL to maintain a strict latency I state and, without WAPL, leaky expression of the LMP proteins occurs.
2024-08-06 | GSE264502 | GEO
Project description:Epstein-Barr virus (EBV) is a ubiquitous human pathogen that is etiologically linked to several cancers and has been connected to multiple sclerosis. EBV persists in its human hosts through a biphasic replication cycle that depends on three latency stages. Understanding the host mechanisms that contribute to the tight regulation of viral gene expression in the discrete states of latency III, latency II, and latency I is important for developing therapeutic approaches for treating EBV positive cancers. Regulation of the chromatin structure of the EBV genome by cohesin and CTCF plays a role in this latency type switching. However, the function of the cohesin release factor WAPL had not previously been understood. In this study, we employ RNA-seq combined with immunofluorescence analysis to determine that the cohesin release factor WAPL plays a role specifically in inhibiting the expression of the oncogenic latent membrane proteins LMP-1 and LMP-2A. Through a combination of Hi-ChIP and ChIP-qPCR, we uncover that WAPL loss alters the looping interactions within the EBV genome and alters the histone modifications present at the LMP promoter. We propose that EBV coopts WAPL to maintain a latency I state and, without WAPL, leaky expression of the LMP proteins occurs.
2024-08-06 | GSE248335 | GEO
Project description:Epstein-Barr virus (EBV) is a ubiquitous human pathogen that is etiologically linked to several cancers and has been connected to multiple sclerosis. EBV persists in its human hosts through a biphasic replication cycle that depends on three latency stages. Understanding the host mechanisms that contribute to the tight regulation of viral gene expression in the discrete states of latency III, latency II, and latency I is important for developing therapeutic approaches for treating EBV positive cancers. Regulation of the chromatin structure of the EBV genome by cohesin and CTCF plays a role in this latency type switching. However, the function of the cohesin release factor WAPL had not previously been understood. In this study, we employ RNA-seq combined with immunofluorescence analysis to determine that the cohesin release factor WAPL plays a role specifically in inhibiting the expression of the oncogenic latent membrane proteins LMP-1 and LMP-2A. Through a combination of Hi-ChIP and ChIP-qPCR, we uncover that WAPL loss alters the looping interactions within the EBV genome and alters the histone modifications present at the LMP promoter. We propose that EBV coopts WAPL to maintain a latency I state and, without WAPL, leaky expression of the LMP proteins occurs.
2024-08-06 | GSE248336 | GEO
Project description:The cellular microRNA, miR-155 has been shown to be involved in lymphocyte activation and is expressed in EBV infected cells displaying type III latency gene expression but not type I latency gene expression. We show here that the elevated levels of miR-155 in type III latency cells is due to EBV gene expression and not epigenetic differences in cell lines tested and we show that expression in EBV infected cells requires a conserved AP-1 element in the miR-155 promoter. Gene expression analysis was carried out in a type I latency cell line transduced with a miR-155 expressing retrovirus. This analysis identified both miR-155 suppressed and induced cellular mRNAs and suggested that in addition to direct targeting of 3’ UTRs, miR-155 alters gene expression in part through the alteration of signal transduction pathways. 3’ UTR reporter analysis of predicted miR-155 target genes identified the transcriptional regulatory genes, BACH1, ZIC3, HIVEP2, CEBPB, ZNF652, ARID2, and SMAD5 as miR-155 targets. Western blot analysis of the most highly suppressed of these, BACH1, showed lower expression in cells transduced with a miR-155 retrovirus. Inspection of the promoters from genes regulated in EBV infected cells and in cells infected with a miR-155 retrovirus identified potential binding sequences for BACH1 and ZIC3. Together, these experiments suggest that the induction of miR-155 by EBV contributes to EBV mediated signaling in part through the modulation of transcriptional regulatory factors. Keywords: Gene expression analysis in EBV positive vs EBV negative cells
2008-03-18 | GSE10863 | GEO
Project description:EBV-positive cell lines were assayed for expression of EBV miRNAs. The names of the miRNAs are from miRBase from Fall 2007. Microarray probes are tandem complements of the mature miRNA sequence. We assayed Burkitt's lymphoma (BL), Nasopharyngeal carcinoma, post-transplant lymphoproliferative disease (PTLD), primary effusion lymphoma, and lymphoblastoid cell lines. We also assayed primary B cells that were infected with the B95-8 strain of EBV, which was found to express EBV miRNAs as early as 20 hours post infection. We have found PTLD and BLs from HIV-positive donors both express EBV miRNAs. These types of cell lines have not previously been found to express viral miRNAs. We have found that cells that support type I and type II latency express only the BART miRNAs, whereas cells that support type III latency express BART and BHRF1 miRNAs. Furthermore, BL cell lines that spontaneously lose EBV express levels of the viral miRNAs that are at least 5-fold lower than cell lines that do not lose EBV.
2008-12-01 | GSE12014 | GEO
Project description:Epstein Barr Virus (EBV) is a potentially oncogenic gammaherpesvirus that establishes a chronic, latent infection in memory B cells. The EBV genome persists in infected host cells as a chromatinized episome and is subject to chromatin-mediated regulation. Binding of the host insulator protein CTCF to the EBV genome has an established role in maintaining viral latency type. CTCF is post-translationally modified by the host enzyme PARP1. PARP1, or Poly(ADP-ribose) polymerase 1, catalyzes the transfer of a poly(ADP-ribose) (PAR) moiety from NAD+ onto acceptor proteins including itself, histone proteins, and CTCF. PARylation of CTCF by PARP1 can affect CTCF’s insulator activity, DNA binding capacity, and ability to form chromatin loops. Both PARP1 and CTCF have been implicated in the regulation of EBV latency and lytic reactivation. Thus, we predicted that pharmacological inhibition with PARP1 inhibitors would affect EBV latency type through a chromatin-specific mechanism. Here, we show that PARP1 and CTCF colocalize at specific sites throughout the EBV genome, and provide evidence to suggest that PARP1 acts to stabilize CTCF binding and maintain the open chromatin landscape at the active Cp promoter during type III latency. Further, PARP1 activity is important in maintaining latency type-specific viral gene expression. The data presented here provide a rationale for the use of PARP inhibitors in the treatment of EBV-associated cancers exhibiting type III latency, and could ultimately contribute to an EBV-specific treatment strategy for AIDS-related or post-transplant lymphomas.
2018-06-27 | GSE115829 | GEO
Project description:Several cellular factors, including the nuclear lamina, regulate chromatin composition and architecture. While the interaction of the viral genome with the nuclear lamina has been studied in the context of EBV lytic reactivation, the role of the nuclear lamina in controlling EBV latency has not been investigated. Here, we report that the nuclear lamina is an essential epigenetic regulator of the EBV episome.
2022-03-18 | GSE198954 | GEO