The Nuclear Lamina Binds the EBV Genome During Latency and Regulates Viral Gene Expression
Ontology highlight
ABSTRACT:
ORGANISM(S): human gammaherpesvirus 4
PROVIDER: GSE198954 | GEO | 2022/03/18
REPOSITORIES: GEO
Similar Datasets
Project description:Approximately 90% of the world population is infected with EBV and carries the virus in a silent, asymptomatic state for life. In immunocompromised individuals, EBV infection can cause B-cell transformation and malignancies. One approach to control EBV infectivity is by changing the expression of viral genes. We are interested in how epigenetics contributes to regulating the gene expression patterns adopted by EBV during latency. The host’s hijacking is a well know strategy adopted by viruses to modify the epigenome, the transcriptome and the proteome of the host with the aim to survive and remain silent in the host. We observed that in B cells, EBV infection mimics antigen-mediated activation, resulting in the induction of specific proteins named Lamin A/C. Lamins have multiple and central roles: they provide nuclear physical support, anchor the heterochromatin to the nuclear periphery and seem to play a role in several nuclear functions requiring the chromatin structure rearrangement. The interaction with lamins has already been studied in the context of EBV lytic reactivation, but their role in the control of the EBV latency states and as epigenetic regulators of different EBV genes expression profiles has not been investigated. The binding of the Lamin AC to important regulatory regions of EBV genome was assessed through ChIP-Seq, and gene expression (RNA-Seq) profiles were evaluated in wild type and Lamin AC KO cell lines. Differences in protein and RNA expressions in B cells activated by using both EBV and a simulation of the immune response were analyzed. Our data suggest two main conclusions: lamins might contribute to the epigenetic control of EBV genes expression during latency changing the interaction of the host structural proteins with key regulatory regions in the viral genome and a possible mechanism with who EBV modifies the nucleus and hijacks cellular mechanisms.
2022-04-08 | GSE198412 | GEO
Project description:Approximately 90% of the world population is infected with EBV and carries the virus in a silent, asymptomatic state for life. In immunocompromised individuals, EBV infection can cause B-cell transformation and malignancies. One approach to control EBV infectivity is by changing the expression of viral genes. We are interested in how epigenetics contributes to regulating the gene expression patterns adopted by EBV during latency. The host’s hijacking is a well know strategy adopted by viruses to modify the epigenome, the trascriptome and the proteome of the host with the aim to survive and remain silent in the host. We observed that in B cells, EBV infection mimics antigen-mediated activation, resulting in the induction of specific proteins named Lamin A/C. Lamins have multiple and central roles they: provide nuclear physical support; anchor the heterochromatin to the nuclear periphery and seem to play a role in several nuclear functions requing the chromatin structure rearrangement. The interaction with lamins has already been study in the context of EBV lytic reactivation, but their role in the control of the EBV latency states and as epigenetic regulators of different EBV genes expression profiles as not been investigated. The binding of the Lamin AC to important regulatory regions of EBV genome was assessed through ChIP-Seq and, and gene expression (RNA-Seq) profiles, were evaluated in wild type and Lamin AC KO cell lines. Differences in protein and RNA expressions in B cells activated by using both EBV and a simulation of the immune response were analyzed. Our data suggest two main conclusion: lamins might contribute to the epigenetic control of EBV genes expression during latency changing the interaction of the host structural proteins with key regulatory regions in the viral genome and a possible mechanism with who EBV modifies the nucleus and hijacks cellular mechanisms.
2022-03-11 | GSE181012 | GEO
Project description:Nuclear Lamina binds the EBV genome during latency and regulates viral gene expression
| PRJNA814988 | ENA
Project description:The Nuclear Lamina Binds the EBV Genome During Latency and Regulates Viral Gene Expression
| PRJNA817564 | ENA
Project description:Nuclear Lamina binds the EBV genome during latency and regulates viral gene expression [RNA-seq]
| PRJNA750410 | ENA
Project description:Nuclear lamina binds the EBV genome during latency and regulates viral gene expression [Hi-C]
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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:Epidemiological studies have demonstrated that Epstein-Barr virus (EBV) is a known etiologic risk factor, and perhaps prerequisite, for the development of MS. EBV establishes life-long latent infection in a subpopulation of memory B cells. Although the role of memory B cells in the pathobiology of MS is well established, studies characterizing EBV-associated mechanisms of B cell inflammation and disease pathogenesis in EBV (+) B cells from MS patients are limited. Accordingly, we analyzed spontaneous lymphoblastoid cell lines (SLCLs) from multiple sclerosis patients and healthy controls to study host-virus interactions in B cells, in the context of an individual’s endogenous EBV. We identify differences in EBV gene expression and regulation of both viral and cellular genes in SLCLs. Our data suggest that EBV latency is dysregulated in MS SLCLs with increased lytic gene expression observed in MS patient B cells, especially those generated from samples obtained during “active” disease. Moreover, we show increased inflammatory gene expression and cytokine production in MS patient SLCLs and demonstrate that tenofovir alafenamide, an antiviral that targets EBV replication, decreases EBV viral loads, EBV lytic gene expression, and EBV-mediated inflammation in both SLCLs and in a mixed lymphocyte assay. Collectively, these data suggest that dysregulation of EBV latency in MS drives a pro-inflammatory, pathogenic phenotype in memory B cells and that this response can be attenuated by suppressing EBV lytic activation. This study provides further support for the development of antiviral agents that target EBV-infection for use in MS.
2023-12-21 | GSE221623 | GEO
Project description:Epstein-Barr virus (EBV) uses a biphasic lifecycle of latency and lytic reactivation to infect >95% of adults worldwide. Despite its central role in EBV persistence and oncogenesis, much remains unknown about how EBV latency is maintained. We used a human genome-wide CRISPR/Cas9 screen to identify that the nuclear protein SFPQ was critical for latency. SFPQ supported expression of linker histone H1, which stabilizes nucleosomes and regulates nuclear architecture, but has not been previously implicated in EBV gene regulation. H1 occupied latent EBV genomes, including the immediate early gene BZLF1 promoter. Upon reactivation, SFPQ was sequestered into sub-nuclear puncta, and EBV genomic H1 occupancy diminished. Enforced H1 expression blocked EBV reactivation upon SFPQ knockout, confirming it as necessary downstream of SFPQ. SFPQ knockout triggered reactivation of EBV in B and epithelial cells as well as in Kaposi’s Sarcoma Associated Herpesvirus, suggesting a conserved gamma-herpesvirus role. These findings highlight SFPQ as a major regulator of H1 expression and EBV latency.
2024-04-16 | GSE235265 | GEO
Project description:As a human tumor virus, EBV is present as a latent infection in its associated malignancies where genetic and epigenetic changes have been shown to impede cellular differentiation and viral reactivation. One such change is increased levels of the Wnt signaling effector, lymphoid enhancer binding factor 1 (LEF1) following EBV epithelial infection. In silico analysis of EBV type 1 and 2 genomes identified over 20 Wnt-response elements suggesting that LEF1 may directly bind the EBV genome and regulate the viral life cycle. Using CUT&RUN-seq, LEF1 was shown to bind the latent EBV genome at various sites encoding viral lytic products that included the immediate early transactivator BZLF1 and viral primase BSLF1 genes. SiRNA depletion of specific LEF1 isoforms revealed that the alternative-promoter derived isoform with an N-terminal truncation (∆N LEF1) transcriptionally repressed lytic genes associated with LEF1 binding. Furthermore, forced expression of the ∆N LEF1 isoform antagonized EBV reactivation from latency. The LEF1 mediated repression requires histone deacetylase activity through either recruitment or a direct intrinsic histone deacetylase activity. SiRNA depletion of LEF1 resulted in increased histone 3 lysine 9 and lysine 27 acetylation at LEF1 binding sites and across the EBV genome. These results support a novel role for LEF1 in maintaining EBV latency and restriction viral reactivation via repressive chromatin remodeling of critical lytic cycle factors
2023-12-05 | GSE245534 | GEO