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CpG-methylation regulates a class of Epstein-Barr virus promoters.
PLoS Pathog 2010; 6(9):e1001114PP

Abstract

DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian gene regulation. In general, cytosine-phosphatidyl-guanosine (CpG)-methylated promoters are transcriptionally repressed and nuclear proteins such as MECP2, MBD1, MBD2, and MBD4 bind CpG-methylated DNA and contribute to epigenetic silencing. Methylation of viral DNA also regulates gene expression of Epstein-Barr virus (EBV), which is a model of herpes virus latency. In latently infected human B cells, the viral DNA is CpG-methylated, the majority of viral genes is repressed and virus synthesis is therefore abrogated. EBV's BZLF1 encodes a transcription factor of the AP-1 family (Zta) and is the master gene to overcome viral gene repression. In a genome-wide screen, we now identify and characterize those viral genes, which Zta regulates. Among them are genes essential for EBV's lytic phase, which paradoxically depend on strictly CpG-methylated promoters for their Zta-induced expression. We identified novel DNA recognition motifs, termed meZRE (methyl-Zta-responsive element), which Zta selectively binds in order to 'read' DNA in a methylation- and sequence-dependent manner unlike any other known protein. Zta is a homodimer but its binding characteristics to meZREs suggest a sequential, non-palindromic and bipartite DNA recognition element, which confers superior DNA binding compared to CpG-free ZREs. Our findings indicate that Zta has evolved to transactivate cytosine-methylated, hence repressed, silent promoters as a rule to overcome epigenetic silencing.

Authors+Show Affiliations

Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20886097

Citation

Bergbauer, Martin, et al. "CpG-methylation Regulates a Class of Epstein-Barr Virus Promoters." PLoS Pathogens, vol. 6, no. 9, 2010, pp. e1001114.
Bergbauer M, Kalla M, Schmeinck A, et al. CpG-methylation regulates a class of Epstein-Barr virus promoters. PLoS Pathog. 2010;6(9):e1001114.
Bergbauer, M., Kalla, M., Schmeinck, A., Göbel, C., Rothbauer, U., Eck, S., ... Hammerschmidt, W. (2010). CpG-methylation regulates a class of Epstein-Barr virus promoters. PLoS Pathogens, 6(9), pp. e1001114. doi:10.1371/journal.ppat.1001114.
Bergbauer M, et al. CpG-methylation Regulates a Class of Epstein-Barr Virus Promoters. PLoS Pathog. 2010 Sep 23;6(9):e1001114. PubMed PMID: 20886097.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CpG-methylation regulates a class of Epstein-Barr virus promoters. AU - Bergbauer,Martin, AU - Kalla,Markus, AU - Schmeinck,Anne, AU - Göbel,Christine, AU - Rothbauer,Ulrich, AU - Eck,Sebastian, AU - Benet-Pagès,Anna, AU - Strom,Tim M, AU - Hammerschmidt,Wolfgang, Y1 - 2010/09/23/ PY - 2010/05/25/received PY - 2010/08/20/accepted PY - 2010/10/2/entrez PY - 2010/10/5/pubmed PY - 2011/2/15/medline SP - e1001114 EP - e1001114 JF - PLoS pathogens JO - PLoS Pathog. VL - 6 IS - 9 N2 - DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian gene regulation. In general, cytosine-phosphatidyl-guanosine (CpG)-methylated promoters are transcriptionally repressed and nuclear proteins such as MECP2, MBD1, MBD2, and MBD4 bind CpG-methylated DNA and contribute to epigenetic silencing. Methylation of viral DNA also regulates gene expression of Epstein-Barr virus (EBV), which is a model of herpes virus latency. In latently infected human B cells, the viral DNA is CpG-methylated, the majority of viral genes is repressed and virus synthesis is therefore abrogated. EBV's BZLF1 encodes a transcription factor of the AP-1 family (Zta) and is the master gene to overcome viral gene repression. In a genome-wide screen, we now identify and characterize those viral genes, which Zta regulates. Among them are genes essential for EBV's lytic phase, which paradoxically depend on strictly CpG-methylated promoters for their Zta-induced expression. We identified novel DNA recognition motifs, termed meZRE (methyl-Zta-responsive element), which Zta selectively binds in order to 'read' DNA in a methylation- and sequence-dependent manner unlike any other known protein. Zta is a homodimer but its binding characteristics to meZREs suggest a sequential, non-palindromic and bipartite DNA recognition element, which confers superior DNA binding compared to CpG-free ZREs. Our findings indicate that Zta has evolved to transactivate cytosine-methylated, hence repressed, silent promoters as a rule to overcome epigenetic silencing. SN - 1553-7374 UR - https://www.unboundmedicine.com/medline/citation/20886097/CpG_methylation_regulates_a_class_of_Epstein_Barr_virus_promoters_ L2 - http://dx.plos.org/10.1371/journal.ppat.1001114 DB - PRIME DP - Unbound Medicine ER -