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            -Repression of Protein Expression Dependent on the Epstein-Barr Virus Promoter Wp during Latency

Hughes, David J.; Dickerson, Carol A.; Shaner, Marie S.; Sample, Clare E.; Sample, Jeffery T.

doi:10.1128/jvi.05158-11

Cited by 14 publications

(16 citation statements)

References 83 publications

(96 reference statements)

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“…Upon superinfection with wt rEBV, these BL cells retain the endogenous viral genome in a latency I program (EBNA1 expression from Qp), and the superinfecting-virus genomes transition from latency III to I over the course of 1 to 2 months (14). Consistent with the prediction of Chau et al (6), we found that our ⌬CTCF rEBV exhibited delayed silencing of Cp, and in one of two superinfected lines obtained, Cp usage has persisted beyond 14 months.…”

Section: Discussionsupporting

confidence: 78%

“…In contrast, we have found that following superinfection, the frequency of genome integration is much lower or nonexistent, and the conversion from latency III to I, at both the mRNA and protein levels, is generally complete at 1 month postsuperinfection. Importantly, the EBNA gene transcriptional program of the endogenous EBV genomes within superinfected Kem I, as well as those within superinfected Akata BL cells (9), remains latency I, whereas transcription from the superinfecting-virus genomes appears to transition from latency III to I (14). Thus, establishment of restricted latency by the superinfecting virus would appear to recapitulate that which is believed to occur within normal B cells infected in vivo.…”

Section: Ctcf Contributes To Establishment Of Restricted Latencymentioning

confidence: 85%

“…Total cellular RNA was extracted using RNA-BEE (Tel-Test) according to the manufacturer's instructions and treated with RQ1-DNase (Promega) to remove residual DNA. cDNA was generated from 2 g total RNA in 20-l reaction mixtures with 200 U SuperScript III reverse transcriptase (RT) (Invitrogen) according to the manufacturer's instructions, using either 0.1 pmol gene-specific primer (GSP) for EBV transcripts or 5 ng oligo(dT) [12][13][14][15][16][17][18] (Invitrogen) for GAPDH (glyceraldehyde-3-phosphate dehydrogenase) and DNMT3B mRNAs. Nucleotide sequences and descriptions of primers used for RT-PCR are provided in Table S1 in the supplemental material.…”

Section: Methodsmentioning

confidence: 99%

“…Likewise, stable knockdown of CTCF did not result in reactivation of Cp or latency III-specific EBV protein expression in BL cells that normally maintain latency I. Most importantly, however, employing a BL cell superinfection model that we have recently developed for such studies (14), a mutant recombinant EBV (rEBV) deleted for the previously identified Cp CTCF binding site exhibited delayed silencing of Cp in transitioning from latency III to I relative to infection with wild-type (wt) rEBV. Thus, our results are consistent with a role for CTCF in the establishment of restricted latency.…”

Section: Pstein-barr Virus (Ebv) Establishes a Lifelong Largely Quiementioning

confidence: 99%

“…Wild-type and ⌬CTCF rEBVs (both encoding GFP and neomycin resistance) were then produced from HEK293 cells (see Materials and Methods) and used to superinfect Kem I BL cells. This B-cell model of EBV infection that we have recently developed (14) has significant advantages over the infection of EBV-negative BL cells to study establishment of restricted latency. Most notably, infection of EBV-negative BL lines frequently results in integration of the EBV genome (15), and the time required to convert from latency III to I can be quite variable (30,63).…”

Section: Ctcf Contributes To Establishment Of Restricted Latencymentioning

confidence: 99%

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Contributions of CTCF and DNA Methyltransferases DNMT1 and DNMT3B to Epstein-Barr Virus Restricted Latency

Hughes

Marendy

Dickerson

et al. 2012

J Virol

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Establishment of persistent Epstein-Barr virus (EBV) infection requires transition from a program of full viral latency gene expression (latency III) to one that is highly restricted (latency I and 0) within memory B lymphocytes. It is well established that DNA methylation plays a critical role in EBV gene silencing, and recently the chromatin boundary protein CTCF has been implicated as a pivotal regulator of latency via its binding to several loci within the EBV genome. One notable site is upstream of the common EBNA gene promoter Cp, at which CTCF may act as an enhancer-blocking factor to initiate and maintain silencing of EBNA gene transcription. It was previously suggested that increased expression of CTCF may underlie its potential to promote restricted latency, and here we also noted elevated levels of DNA methyltransferase 1 (DNMT1) and DNMT3B associated with latency I. Within B-cell lines that maintain latency I, however, stable knockdown of CTCF, DNMT1, or DNMT3B or of DNMT1 and DNMT3B in combination did not result in activation of latency III protein expression or EBNA gene transcription, nor did knockdown of DNMTs significantly alter CpG methylation within Cp. Thus, differential expression of CTCF and DNMT1 and -3B is not critical for maintenance of restricted latency. Finally, mutant EBV lacking the Cp CTCF binding site exhibited sustained Cp activity relative to wild-type EBV in a recently developed B-cell superinfection model but ultimately was able to transition to latency I, suggesting that CTCF contributes to but is not necessarily essential for the establishment of restricted latency. E pstein-Barr virus (EBV) establishes a lifelong, largely quiescent (latent) infection within B lymphocytes of its human host.This requires the concerted actions of the viral latency-associated genes, several of which are believed to facilitate a germinal center (GC)-like reaction to promote differentiation of infected B cells into ones phenotypically defined as memory B cells and which serve as the primary reservoir of EBV within persistently infected individuals (reviewed in reference 59). During the establishment of latency in vivo, infected B cells must transition through several programs of EBV latency gene transcription, beginning with expression of the full complement of latency proteins (the latency III program), i.e., six nuclear antigens (EBNAs) and three integral plasma membrane proteins (LMPs), that is associated with a rapid EBV-induced expansion of infected cells. Thereafter, expression proceeds through a more restricted program limited to EBNA1, LMP1, and LMP2 (latency II) and ultimately to a complete restriction of EBV protein expression in the memory B cell (latency 0 [alternatively, the latency program]) (reviewed in reference 44). During subsequent periods of limited cell division, reactivation of expression of the EBV genome-maintenance protein EBNA1 alone (latency I) occurs to ensure against loss of the episomal viral genome (12).With the exception of latency 0, each of the viral latency prog...

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Section: Discussionsupporting

confidence: 78%

Section: Ctcf Contributes To Establishment Of Restricted Latencymentioning

confidence: 85%

Section: Methodsmentioning

confidence: 99%

Section: Pstein-barr Virus (Ebv) Establishes a Lifelong Largely Quiementioning

confidence: 99%

Section: Ctcf Contributes To Establishment Of Restricted Latencymentioning

confidence: 99%

See 3 more Smart Citations

Contributions of CTCF and DNA Methyltransferases DNMT1 and DNMT3B to Epstein-Barr Virus Restricted Latency

Hughes

Marendy

Dickerson

et al. 2012

J Virol

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Epigenetic Alterations in Epstein-Barr Virus-Associated Diseases

Niller

Bánáti

Salamon

et al. 2015

Advances in Experimental Medicine and Biology

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Latent Epstein-Bar virus genomes undergo epigenetic modifications which are dependent on the respective tissue type and cellular phenotype. These define distinct viral epigenotypes corresponding with latent viral gene expression profiles. Viral Latent Membrane Proteins 1 and 2A can induce cellular DNA methyltransferases, thereby influencing the methylation status of the viral and cellular genomes. Therefore, not only the viral genomes carry epigenetic modifications, but also the cellular genomes adopt major epigenetic alterations upon EBV infection. The distinct cellular epigenotypes of EBV-infected cells differ from the epigenotypes of their normal counterparts. In Burkitt lymphoma (BL), nasopharyngeal carcinoma (NPC) and EBV-associated gastric carcinoma (EBVaGC) significant changes in the host cell methylome with a strong tendency towards CpG island hypermethylation are observed. Hypermethylated genes unique for EBVaGC suggest the existence of an EBV-specific "epigenetic signature". Contrary to the primary malignancies carrying latent EBV genomes, lymphoblastoid cells (LCs) established by EBV infection of peripheral B cells in vitro are characterized by a massive genome-wide demethylation and a significant decrease and redistribution of heterochromatic histone marks. Establishing complete epigenomes of the diverse EBV-associated malignancies shall clarify their similarities and differences and further clarify the contribution of EBV to the pathogenesis, especially for the epithelial malignancies, NPC and EBVaGC.

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Genipin as a novel chemical activator of EBV lytic cycle

et al. 2015

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Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus that causes acute infection and establishes life-long latency. EBV causes several human cancers, including Burkitt's lymphoma, nasopharyngeal and gastric carcinoma. Antiviral agents can be categorized as virucides, antiviral chemotherapeutic agents, and immunomodulators. Most antiviral agents affect actively replicating viruses, but not their latent forms. Novel antiviral agents must be active on both the replicating and the latent forms of the virus. Gardenia jasminoides is an evergreen flowering plant belonging to the Rubiaceae family and is most commonly found growing wild in Vietnam, Southern China, Taiwan, Japan, Myanmar, and India. Genipin is an aglycone derived from an iridoid glycoside called geniposide, which is present in large quantities in the fruit of G. jasminoides. In this study, genipin was evaluated for its role as an antitumor and antiviral agent that produces inhibitory effects against EBV and EBV associated gastric carcinoma (EBVaGC). In SNU719 cells, one of EBVaGCs, genipin caused significant cytotoxicity (70 μM), induced methylation on EBV C promoter and tumor suppressor gene BCL7A, arrested cell-cycle progress (S phases), upregulated EBV latent/lytic genes in a dose-dependent manner, stimulated EBV progeny production, activated EBV F promoter for EBV lytic activation, and suppressed EBV infection. These results indicated that genipin could be a promising candidate for antiviral and antitumor agents against EBV and EBVaGC.

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trans -Repression of Protein Expression Dependent on the Epstein-Barr Virus Promoter Wp during Latency

Cited by 14 publications

References 83 publications

Contributions of CTCF and DNA Methyltransferases DNMT1 and DNMT3B to Epstein-Barr Virus Restricted Latency

Contributions of CTCF and DNA Methyltransferases DNMT1 and DNMT3B to Epstein-Barr Virus Restricted Latency

Epigenetic Alterations in Epstein-Barr Virus-Associated Diseases

Genipin as a novel chemical activator of EBV lytic cycle

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