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Evaluation of a prediction protocol to identify potential targets of epigenetic reprogramming by the cancer associated Epstein Barr virus.
PLoS One. 2010 Feb 26; 5(2):e9443.Plos

Abstract

BACKGROUND

Epstein Barr virus (EBV) infects the majority of the human population, causing fatal diseases in a small proportion in conjunction with environmental factors. Following primary infection, EBV remains latent in the memory B cell population for life. Recurrent reactivation of the virus occurs, probably due to activation of the memory B-lymphocytes, resulting in viral replication and re-infection of B-lymphocytes. Methylation of the viral DNA at CpG motifs leads to silencing of viral gene expression during latency. Zta, the key viral protein that mediates the latency/reactivation balance, interacts with methylated DNA. Zta is a transcription factor for both viral and host genes. A sub-set of its DNA binding sites (ZREs) contains a CpG motif, which is recognised in its methylated form. Detailed analysis of the promoter of the viral gene BRLF1 revealed that interaction with a methylated CpG ZRE (RpZRE3) is key to overturning the epigenetic silencing of the gene.

METHODOLOGY AND PRINCIPAL FINDINGS

Here we question whether we can use this information to identify which host genes contain promoters with similar response elements. A computational search of human gene promoters identified 274 targets containing the 7-nucleotide RpZRE3 core element. DNA binding analysis of Zta with 17 of these targets revealed that the flanking context of the core element does not have a profound effect on the ability of Zta to interact with the methylated sites. A second juxtaposed ZRE was observed for one promoter. Zta was able to interact with this site, although co-occupancy with the RpZRE3 core element was not observed.

CONCLUSIONS/SIGNIFICANCE

This research demonstrates 274 human promoters have the potential to be regulated by Zta to overturn epigenetic silencing of gene expression during viral reactivation from latency.

Authors+Show Affiliations

School of Life Sciences, University of Sussex, Brighton, United Kingdom.No 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

20195470

Citation

Flower, Kirsty, et al. "Evaluation of a Prediction Protocol to Identify Potential Targets of Epigenetic Reprogramming By the Cancer Associated Epstein Barr Virus." PloS One, vol. 5, no. 2, 2010, pp. e9443.
Flower K, Hellen E, Newport MJ, et al. Evaluation of a prediction protocol to identify potential targets of epigenetic reprogramming by the cancer associated Epstein Barr virus. PLoS ONE. 2010;5(2):e9443.
Flower, K., Hellen, E., Newport, M. J., Jones, S., & Sinclair, A. J. (2010). Evaluation of a prediction protocol to identify potential targets of epigenetic reprogramming by the cancer associated Epstein Barr virus. PloS One, 5(2), e9443. https://doi.org/10.1371/journal.pone.0009443
Flower K, et al. Evaluation of a Prediction Protocol to Identify Potential Targets of Epigenetic Reprogramming By the Cancer Associated Epstein Barr Virus. PLoS ONE. 2010 Feb 26;5(2):e9443. PubMed PMID: 20195470.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Evaluation of a prediction protocol to identify potential targets of epigenetic reprogramming by the cancer associated Epstein Barr virus. AU - Flower,Kirsty, AU - Hellen,Elizabeth, AU - Newport,Melanie J, AU - Jones,Susan, AU - Sinclair,Alison J, Y1 - 2010/02/26/ PY - 2009/10/14/received PY - 2009/12/02/accepted PY - 2010/3/3/entrez PY - 2010/3/3/pubmed PY - 2010/10/1/medline SP - e9443 EP - e9443 JF - PloS one JO - PLoS ONE VL - 5 IS - 2 N2 - BACKGROUND: Epstein Barr virus (EBV) infects the majority of the human population, causing fatal diseases in a small proportion in conjunction with environmental factors. Following primary infection, EBV remains latent in the memory B cell population for life. Recurrent reactivation of the virus occurs, probably due to activation of the memory B-lymphocytes, resulting in viral replication and re-infection of B-lymphocytes. Methylation of the viral DNA at CpG motifs leads to silencing of viral gene expression during latency. Zta, the key viral protein that mediates the latency/reactivation balance, interacts with methylated DNA. Zta is a transcription factor for both viral and host genes. A sub-set of its DNA binding sites (ZREs) contains a CpG motif, which is recognised in its methylated form. Detailed analysis of the promoter of the viral gene BRLF1 revealed that interaction with a methylated CpG ZRE (RpZRE3) is key to overturning the epigenetic silencing of the gene. METHODOLOGY AND PRINCIPAL FINDINGS: Here we question whether we can use this information to identify which host genes contain promoters with similar response elements. A computational search of human gene promoters identified 274 targets containing the 7-nucleotide RpZRE3 core element. DNA binding analysis of Zta with 17 of these targets revealed that the flanking context of the core element does not have a profound effect on the ability of Zta to interact with the methylated sites. A second juxtaposed ZRE was observed for one promoter. Zta was able to interact with this site, although co-occupancy with the RpZRE3 core element was not observed. CONCLUSIONS/SIGNIFICANCE: This research demonstrates 274 human promoters have the potential to be regulated by Zta to overturn epigenetic silencing of gene expression during viral reactivation from latency. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/20195470/Evaluation_of_a_prediction_protocol_to_identify_potential_targets_of_epigenetic_reprogramming_by_the_cancer_associated_Epstein_Barr_virus_ L2 - http://dx.plos.org/10.1371/journal.pone.0009443 DB - PRIME DP - Unbound Medicine ER -