Epigenetic Control of Viral Life-Cycle by a DNA-Methylation Dependent Transcription Factor

Flower, Kirsty; Thomas, David John; Heather, James; Ramasubramanyan, Sharada; Jones, Susan R.; Sinclair, Alison J.

doi:10.1371/journal.pone.0025922

Cited by 45 publications

(61 citation statements)

References 44 publications

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“…This theoretically provides Zta with the ability to access DNA within the EBV genome even when it has been epigenetically silenced by DNA methylation. We show here that Zta interacts with both origins of lytic replication and with the promoters of BZLF1, BRLF1, and BMRF1 in Akata cells at regions containing predicted ZREs (19). This supports and extends previous reports that Zta interacts with the EBV genome in vivo in other cell types (2,9,26,52).…”

Section: Discussionsupporting

confidence: 90%

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Dynamic Chromatin Environment of Key Lytic Cycle Regulatory Regions of the Epstein-Barr Virus Genome

Ramasubramanyan

Osborn

Flower

et al. 2012

J Virol

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The ability of Epstein-Barr virus (EBV) to establish latency allows it to evade the immune system and to persist for the lifetime of its host; one distinguishing characteristic is the lack of transcription of the majority of viral genes. Entry into the lytic cycle is coordinated by the viral transcription factor, Zta (BZLF1, ZEBRA, and EB1), and downstream effectors, while viral genome replication requires the concerted action of Zta and six other viral proteins at the origins of lytic replication. We explored the chromatin context at key EBV lytic cycle promoters (BZLF1, BRLF1, BMRF1, and BALF5) and the origins of lytic replication during latency and lytic replication. We show that a repressive heterochromatin-like environment (trimethylation of histone H3 at lysine 9 [H3K9me3] and lysine 27 [H3K27me3]), which blocks the interaction of some transcription factors with DNA, encompasses the key early lytic regulatory regions. Epigenetic silencing of the EBV genome is also imposed by DNA methylation during latency. The chromatin environment changes during the lytic cycle with activation of histones H3, H4, and H2AX occurring at both the origins of replication and at the key lytic regulatory elements. We propose that Zta is able to reverse the effects of latency-associated repressive chromatin at EBV early lytic promoters by interacting with Zta response elements within the H3K9me3-associated chromatin and demonstrate that these interactions occur in vivo. Since the interaction of Zta with DNA is not inhibited by DNA methylation, it is clear that Zta uses two routes to overcome epigenetic silencing of its genome.

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Section: Discussionsupporting

confidence: 90%

“…It is a sequencespecific DNA-binding protein, with a promiscuous range of response elements; it can interact with at least 32 sequence variants of a 7-mer sequence (ZREs) (19). Zta has the unusual ability to recognize methylated DNA (2-4, 9, 26); indeed, some ZREs are entirely dependent on methylation for binding.…”

Section: Discussionmentioning

confidence: 99%

Dynamic Chromatin Environment of Key Lytic Cycle Regulatory Regions of the Epstein-Barr Virus Genome

Ramasubramanyan

Osborn

Flower

et al. 2012

J Virol

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“…Instead, a region between positions Ϫ500 and 200 with respect to the transcription start site (TSS) of the EBV genes was defined as the promoter region (11). The binding strength of Zta in the promoter region was measured as the number of reads in this region per million background subtracted total reads.…”

Section: Methodsmentioning

confidence: 99%

“…ChIP-Seq data analysis: metagene analysis. We extracted sequences for 10-kb regions centered on previously published class III and class I ZREs (with and without CpG, respectively) (11). For each data set, the average number of reads/million for positions relative to the binding site were calculated.…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, CpG ZREs have the potential to encode epigenetic information. Attempts to identify Zta binding sites genomewide have employed in vitro DNA binding and chromatin precipitation (ChIP) using either the DNA binding domain of Zta (3) or a motif identification approach (11). These studies identified further CpG ZREs in the EBV genome that display enhanced Zta binding when methylated in vitro.…”

Section: Pstein-barr Virus (Ebv) Is a Ubiquitous Human Herpesvirusmentioning

confidence: 99%

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Genome-Wide Analyses of Zta Binding to the Epstein-Barr Virus Genome Reveals Interactions in both Early and Late Lytic Cycles and an Epigenetic Switch Leading to an Altered Binding Profile

Ramasubramanyan

Kanhere

Osborn

et al. 2012

J Virol

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cThe Epstein-Barr virus (EBV) genome sustains substantial epigenetic modification involving chromatin remodelling and DNA methylation during lytic replication. Zta (ZEBRA, BZLF1), a key regulator of the EBV lytic cycle, is a transcription and replication factor, binding to Zta response elements (ZREs) in target promoters and EBV lytic origins of replication. In vitro, Zta binding is modulated by DNA methylation; a subset of CpG-containing Zta binding sites (CpG ZREs) is bound only in a DNA methylation-dependent manner. The question of how the dynamic epigenetic environment impacts Zta interaction during the EBV lytic cycle is unknown. To address this, we used chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-Seq) to identify Zta binding sites across the EBV genome before and after viral DNA replication. Replication did not alter the association of Zta across many regions of the EBV genome, but a striking reduction in Zta binding occurred at some loci that contain CpG ZREs. Separating Zta-bound DNA into methylated and nonmethylated fractions, we found that promoters that contain CpG ZREs were enriched in the methylated fraction but that Zta binding to promoters lacking CpG ZREs was not reduced. We hypothesize that the loss of DNA methylation on the EBV genome during the lytic cycle causes the reduced binding to CpG ZREs; this may act as a lytic cycle epigenetic switch. However, the epigenetic changes associated with the replicated EBV genome do not affect the interaction of Zta with many loci that are rich in non-CpG ZREs; this leads to sustained binding at these regions.

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Methylation of Epstein–Barr virus Rta promoter in EBV primary infection, reactivation and lymphoproliferation

Germi

Guigue

Lupo

et al. 2016

Journal of Medical Virology

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During Epstein-Barr virus (EBV) latency, the EBV genome is largely silenced by methylation. This silencing is overturned during the switch to the lytic cycle. A key event is the production of the viral protein Zta which binds to three Zta-response elements (ZRE) from the Rta promoter (Rp), two of which (ZRE2 and ZRE3) include three CpG motifs methylated in the latent genome. The bisulphite pyrosequencing reaction was used to quantify the methylation of ZRE2, ZRE3a, and ZRE3b in EBV-positive cell lines and in ex vivo samples of EBV-related diseases, in order to assess whether the level of methylation in these ZREs could provide additional information to viral DNA load and serology in the characterization of EBV-associated diseases. In PBMC from two patients with infectious mononucleosis, over time Rp became increasingly methylated whereas EBV load decreased. In tonsil from patients with chronic tonsillitis, the methylation was less than in EBV-associated tumors, regardless of the viral load. This was even more striking when only the ZRE3a and ZRE3b were considered since some samples presented unbalanced profiles on ZRE2. EBV reactivation in cell culture showed that the reduction in the overall level of methylation was closely related to the production of unmethylated virions. Thus, an assessment of the level of methylation may help to better characterize EBV replication in PBMC and in biopsies with high EBV load, during infectious mononucleosis and EBV-associated cancers. J. Med. Virol. 88:1814-1820, 2016. © 2016 Wiley Periodicals, Inc.

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Epigenetic Control of Viral Life-Cycle by a DNA-Methylation Dependent Transcription Factor

Cited by 45 publications

References 44 publications

Dynamic Chromatin Environment of Key Lytic Cycle Regulatory Regions of the Epstein-Barr Virus Genome

Dynamic Chromatin Environment of Key Lytic Cycle Regulatory Regions of the Epstein-Barr Virus Genome

Genome-Wide Analyses of Zta Binding to the Epstein-Barr Virus Genome Reveals Interactions in both Early and Late Lytic Cycles and an Epigenetic Switch Leading to an Altered Binding Profile

Methylation of Epstein–Barr virus Rta promoter in EBV primary infection, reactivation and lymphoproliferation

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