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, Sharada, Kanhere, Aditi, Osborn, Kay, Flower, Kirsty, Jenner, Richard G and Sinclair, Alison J (2012) 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. Journal of Virology, 86 (23). pp. 12494-12502. ISSN 0022-538X

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Abstract

The 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 a 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 upon Zta interaction during 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 non-methylated fractions, we found that promoters that contain CpG ZREs were enriched in the methylated fraction but Zta binding to promoters lacking CpG ZREs was not. We hypothesise that the loss of DNA methylation on the EBV genome during 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.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science
Depositing User: Deeptima Massey
Date Deposited: 01 Nov 2012 14:55
Last Modified: 19 Jun 2013 08:39
URI: http://sro.sussex.ac.uk/id/eprint/41256
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