Epigenetic Deregulation of the LMP1/LMP2 Locus of Epstein-Barr Virus by Mutation of a Single CTCF-Cohesin Binding Site

Chen, Horng-Shen; Martin, Kayla; Lü, Fang; Lupey, Lena N.; Mueller, Jenna L.; Lieberman, Paul M.; Tempera, Italo

doi:10.1128/jvi.02209-13

Cited by 57 publications

(83 citation statements)

References 61 publications

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“…To determine whether cordycepin affects EBV infection of AGS cells (gastric carcinoma), we performed cell-to-cell coinfection by using AGS [20] and LCL-EBV-GFP B-cell lymphocyte cells [21]. AGS cells (0.625 × 10 6 /well) were seeded in 6-well plates (Corning, Corning, NY, USA).…”

Section: Methodsmentioning

confidence: 99%

Cordycepin is a novel chemical suppressor of Epstein-Barr virus replication

et al. 2014

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Cordyceps species are known to produce numerous active components and are used for diverse medicinal purposes because of their varied physiological activities, including their ability to protect the liver from damage as well as their anticancer, antidepressant, anti-inflammatory, hypoglycemic, antimicrobial effects. Cordycepin, an adenosine derivative, differs from adenosine in that its ribose lacks an oxygen atom at the 3′ position. Several research groups have reported that cordycepin has antiviral activity against several viruses including influenza virus, plant viruses, human immunodeficiency virus (HIV), murine leukemia virus, and Epstein-Barr virus (EBV). In this study, we identify the epigenetic mechanisms by which cordycepin exerts its anti-gammaherpesvirus effects. We show that cordycepin possesses antitumor and antiviral activity against gastric carcinoma and EBV, respectively. A comparison of the CD 50 values of cordycepin and its analogs showed that the lack of a 2′-hydroxyl group in cordycepin was critical for its relatively potent cytotoxicity. Cordycepin treatment decreased the rate of early apoptosis in SNU719 cells by up to 64%, but increased late apoptosis/necrosis by up to 31%. Interestingly, cordycepin increased BCL7A methylation in SNU719 cells by up to 58% and decreased demethylation by up to 37%. Consistent with these changes in methylation, cordycepin treatment significantly downregulated most EBV genes tested. Under the same conditions, cordycepin significantly decreased the frequency of Q and F promoter usage, and H3K4me3 histone enrichment was significantly reduced at several important EBV genomic loci. Extracellular and intracellular EBV genome copy numbers were reduced by up to 55% and 30%, respectively, in response to 125 µM cordycepin treatment.Oncoscience 867 www.impactjournals.com/oncoscience

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Section: Methodsmentioning

confidence: 99%

Cordycepin is a novel chemical suppressor of Epstein-Barr virus replication

et al. 2014

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“…Similarly, different variants of Epstein-Barr virus latency programs were found to depend on the assembly of alternate spatial configurations of the viral genome (Tempera et al 2011). The choice between these configurations is controlled by CTCF (Chen et al 2014). In the both abovementioned cases, the alternate spatial configurations of the genomic domains were attributed to different cell populations.…”

Section: Linear or Three-dimensional?mentioning

confidence: 96%

3D genomics imposes evolution of the domain model of eukaryotic genome organization

Razin

Vassetzky

2016

Chromosoma

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The hypothesis that the genome is composed of a patchwork of structural and functional domains (units) that may be either active or repressed was proposed almost 30 years ago. Here, we examine the evolution of the domain model of eukaryotic genome organization in view of the expansion of genome-scale techniques in the twenty-first century that have provided us with a wealth of information on genome organization, folding, and functioning.

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“…Chen et al reported that deletion of a CTCF binding site in the LMP1/LMP2 control region of the EBV genome increased the levels of both circular and linear viral genomes in the lymphoid cell lines, although the expression of the immediate-early protein Zta was unaltered (28). Similarly, deletion of the CTCF binding site in KSHV LCR led to increased expression of the lytic loci K14 and ORF74, suggesting that CTCF plays a role in restricting lytic gene expression (24).…”

Section: Discussionmentioning

confidence: 99%

Epstein-Barr Virus Rta-Mediated Accumulation of DNA Methylation Interferes with CTCF Binding in both Host and Viral Genomes

Chen

Chang

et al. 2017

J Virol

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Rta, an Epstein-Barr virus (EBV) immediate-early protein, reactivates viral lytic replication that is closely associated with tumorigenesis. In previous studies, we demonstrated that in epithelial cells Rta efficiently induced cellular senescence, which is an irreversible G 1 arrest likely to provide a favorable environment for productive replications of EBV and Kaposi's sarcoma-associated herpesvirus (KSHV). To restrict progression of the cell cycle, Rta simultaneously upregulates CDK inhibitors and downregulates MYC, CCND1, and JUN, among others. Rta has long been known as a potent transcriptional activator, thus its role in gene repression is unexpected. In silico analysis revealed that the promoter regions of MYC, CCND1, and JUN are common in (i) the presence of CpG islands, (ii) strong chromatin immunoprecipitation (ChIP) signals of CCCTC-binding factor (CTCF), and (iii) having at least one Rta binding site. By combining ChIP assays and DNA methylation analysis, here we provide evidence showing that Rta binding accumulated CpG methylation and decreased CTCF occupancy in the regulatory regions of MYC, CCND1, and JUN, which were associated with downregulated gene expression. Stable residence of CTCF in the viral latency and reactivation control regions is a hallmark of viral latency. Here, we observed that Rta-mediated decreased binding of CTCF in the viral genome is concurrent with virus reactivation. Via interfering with CTCF binding, in the host genome Rta can function as a transcriptional repressor for gene silencing, while in the viral genome Rta acts as an activator for lytic gene loci by removing a topological constraint established by CTCF.IMPORTANCE CTCF is a multifunctional protein that variously participates in gene expression and higher-order chromatin structure of the cellular and viral genomes. In certain loci of the genome, CTCF occupancy and DNA methylation are mutually exclusive. Here, we demonstrate that the Epstein-Barr virus (EBV) immediate-early protein, Rta, known to be a transcriptional activator, can also function as a transcriptional repressor. Via enriching CpG methylation and decreasing CTCF reloading, Rta binding efficiently shut down the expression of MYC, CCND1, and JUN, thus impeding cell cycle progression. Rta-mediated disruption of CTCF binding was also detected in the latency/reactivation control regions of the EBV genome, and this in turn led to viral lytic cycle progression. As emerging evidence indicates that a methylated EBV genome is a preferable substrate for EBV Zta, the other immediate-early protein, our results suggest a mechanistic link in understanding the molecular processes of viral latent-lytic switch.KEYWORDS Epstein-Barr virus, immediate-early protein Rta, lytic cycle reactivation, CTCF, DNA methylation, cell cycle arrest, genome topology, immediate-early protein Rta

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Epigenetic Deregulation of the LMP1/LMP2 Locus of Epstein-Barr Virus by Mutation of a Single CTCF-Cohesin Binding Site

Cited by 57 publications

References 61 publications

Cordycepin is a novel chemical suppressor of Epstein-Barr virus replication

Cordycepin is a novel chemical suppressor of Epstein-Barr virus replication

3D genomics imposes evolution of the domain model of eukaryotic genome organization

Epstein-Barr Virus Rta-Mediated Accumulation of DNA Methylation Interferes with CTCF Binding in both Host and Viral Genomes

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