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CpG-methylation regulates a class of Epstein-Barr virus promoters

PLoS Pathogens, ISSN: 1553-7366, Vol: 6, Issue: 9, Page: e1001114
2010
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Article Description

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. © 2010 Bergbauer et al.

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http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=78149302949&origin=inward; http://dx.doi.org/10.1371/journal.ppat.1001114; http://www.ncbi.nlm.nih.gov/pubmed/20886097; https://dx.plos.org/10.1371/journal.ppat.1001114; https://dx.plos.org/10.1371/journal.ppat.1001114.g008; http://dx.doi.org/10.1371/journal.ppat.1001114.g008; https://dx.plos.org/10.1371/journal.ppat.1001114.g009; http://dx.doi.org/10.1371/journal.ppat.1001114.g009; https://dx.plos.org/10.1371/journal.ppat.1001114.t001; http://dx.doi.org/10.1371/journal.ppat.1001114.t001; https://dx.plos.org/10.1371/journal.ppat.1001114.g006; http://dx.doi.org/10.1371/journal.ppat.1001114.g006; https://dx.plos.org/10.1371/journal.ppat.1001114.g007; http://dx.doi.org/10.1371/journal.ppat.1001114.g007; https://dx.plos.org/10.1371/journal.ppat.1001114.g005; http://dx.doi.org/10.1371/journal.ppat.1001114.g005; https://dx.plos.org/10.1371/journal.ppat.1001114.g001; http://dx.doi.org/10.1371/journal.ppat.1001114.g001; https://dx.plos.org/10.1371/journal.ppat.1001114.g004; http://dx.doi.org/10.1371/journal.ppat.1001114.g004; https://dx.plos.org/10.1371/journal.ppat.1001114.g003; http://dx.doi.org/10.1371/journal.ppat.1001114.g003; https://dx.plos.org/10.1371/journal.ppat.1001114.g002; http://dx.doi.org/10.1371/journal.ppat.1001114.g002; https://dx.doi.org/10.1371/journal.ppat.1001114.g002; https://journals.plos.org/plospathogens/article/figure?id=10.1371/journal.ppat.1001114.g002; https://dx.doi.org/10.1371/journal.ppat.1001114; https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1001114; https://dx.doi.org/10.1371/journal.ppat.1001114.g006; https://journals.plos.org/plospathogens/article/figure?id=10.1371/journal.ppat.1001114.g006; https://dx.doi.org/10.1371/journal.ppat.1001114.g008; https://journals.plos.org/plospathogens/article/figure?id=10.1371/journal.ppat.1001114.g008; https://dx.doi.org/10.1371/journal.ppat.1001114.g001; https://journals.plos.org/plospathogens/article/figure?id=10.1371/journal.ppat.1001114.g001; https://dx.doi.org/10.1371/journal.ppat.1001114.g004; https://journals.plos.org/plospathogens/article/figure?id=10.1371/journal.ppat.1001114.g004; https://dx.doi.org/10.1371/journal.ppat.1001114.g005; https://journals.plos.org/plospathogens/article/figure?id=10.1371/journal.ppat.1001114.g005; https://dx.doi.org/10.1371/journal.ppat.1001114.t001; https://journals.plos.org/plospathogens/article/figure?id=10.1371/journal.ppat.1001114.t001; https://dx.doi.org/10.1371/journal.ppat.1001114.g009; https://journals.plos.org/plospathogens/article/figure?id=10.1371/journal.ppat.1001114.g009; https://dx.doi.org/10.1371/journal.ppat.1001114.g003; https://journals.plos.org/plospathogens/article/figure?id=10.1371/journal.ppat.1001114.g003; https://dx.doi.org/10.1371/journal.ppat.1001114.g007; https://journals.plos.org/plospathogens/article/figure?id=10.1371/journal.ppat.1001114.g007; http://dx.plos.org/10.1371/journal.ppat.1001114.t001; http://dx.plos.org/10.1371/journal.ppat.1001114.g002; http://dx.plos.org/10.1371/journal.ppat.1001114.g009; http://dx.plos.org/10.1371/journal.ppat.1001114.g003; http://dx.plos.org/10.1371/journal.ppat.1001114.g008; http://dx.plos.org/10.1371/journal.ppat.1001114; https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1001114&type=printable; http://dx.plos.org/10.1371/journal.ppat.1001114.g005; http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1001114; http://dx.plos.org/10.1371/journal.ppat.1001114.g006; http://www.plosone.org/article/metrics/info:doi/10.1371/journal.ppat.1001114; http://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1001114&type=printable; http://dx.plos.org/10.1371/journal.ppat.1001114.g007; http://journals.plos.org/plospathogens/article?id=10.1371%2Fjournal.ppat.1001114; http://dx.plos.org/10.1371/journal.ppat.1001114.g004; http://dx.plos.org/10.1371/journal.ppat.1001114.g001

Martin Bergbauer; Markus Kalla; Anne Schmeinck; Christine Göbel; Ulrich Rothbauer; Sebastian Eck; Anna Benet-Pagès; Tim M. Strom; Wolfgang Hammerschmidt; Samuel H. Speck

Public Library of Science (PLoS)

Immunology and Microbiology; Biochemistry, Genetics and Molecular Biology

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