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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.
J Virol. 2012 Dec; 86(23):12494-502.JV

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 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.

Authors+Show Affiliations

School of Life Sciences, University of Sussex, Brighton, E. Sussex, United Kingdom.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23015699

Citation

Ramasubramanyan, Sharada, et al. "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, vol. 86, no. 23, 2012, pp. 12494-502.
Ramasubramanyan S, Kanhere A, Osborn K, et al. 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. J Virol. 2012;86(23):12494-502.
Ramasubramanyan, S., Kanhere, A., Osborn, K., Flower, K., Jenner, R. G., & Sinclair, A. 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), 12494-502. https://doi.org/10.1128/JVI.01705-12
Ramasubramanyan S, et al. 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. J Virol. 2012;86(23):12494-502. PubMed PMID: 23015699.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Ramasubramanyan,Sharada, AU - Kanhere,Aditi, AU - Osborn,Kay, AU - Flower,Kirsty, AU - Jenner,Richard G, AU - Sinclair,Alison J, Y1 - 2012/09/26/ PY - 2012/9/28/entrez PY - 2012/9/28/pubmed PY - 2013/1/15/medline SP - 12494 EP - 502 JF - Journal of virology JO - J. Virol. VL - 86 IS - 23 N2 - 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 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. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/23015699/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_ L2 - http://jvi.asm.org/cgi/pmidlookup?view=long&pmid=23015699 DB - PRIME DP - Unbound Medicine ER -