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

Flower, K; Thomas, D; Heather, J; Ramasubramanyan, S; Jones, S; Sinclair, AJ; (2011) Epigenetic Control of Viral Life-Cycle by a DNA-Methylation Dependent Transcription Factor. PLOS ONE , 6 (10) , Article e25922. 10.1371/journal.pone.0025922. Green open access

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Abstract

Epstein-Barr virus (EBV) encoded transcription factor Zta (BZLF1, ZEBRA, EB1) is the prototype of a class of transcription factor (including C/EBPalpha) that interact with CpG-containing DNA response elements in a methylation-dependent manner. The EBV genome undergoes a biphasic methylation cycle; it is extensively methylated during viral latency but is reset to an unmethylated state following viral lytic replication. Zta is expressed transiently following infection and again during the switch between latency and lytic replication. The requirement for CpG-methylation at critical Zta response elements (ZREs) has been proposed to regulate EBV replication, specifically it could aid the activation of viral lytic gene expression from silenced promoters on the methylated genome during latency in addition to preventing full lytic reactivation from the non-methylated EBV genome immediately following infection. We developed a computational approach to predict the location of ZREs which we experimentally assessed using in vitro and in vivo DNA association assays. A remarkably different binding motif is apparent for the CpG and non-CpG ZREs. Computational prediction of the location of these binding motifs in EBV revealed that the majority of lytic cycle genes have at least one and many have multiple copies of methylation-dependent CpG ZREs within their promoters. This suggests that the abundance of Zta protein coupled with the methylation status of the EBV genome act together to co-ordinate the expression of lytic cycle genes at the majority of EBV promoters.

Type: Article
Title: Epigenetic Control of Viral Life-Cycle by a DNA-Methylation Dependent Transcription Factor
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0025922
Publisher version: http://dx.doi.org/10.1371/journal.pone.0025922
Language: English
Additional information: © 2011 Flower et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This research was supported by grants from the Wellcome Trust, United Kingdom, and University of Sussex. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/1341817
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