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Bergbauer, M. ; Kalla, M. ; Schmeinck, A. ; Göbel, C. ; Rothbauer, U.* ; Eck, S. ; Benet-Pagès, A. ; Strom, T.M. ; Hammerschmidt, W.

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

PLoS Pathog. 6, e1001114 (2010)
Publ. Version/Full Text Volltext DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords CREB-BINDING-PROTEIN; CHIP-SEQ DATA; LYTIC CYCLE; TRANSCRIPTION FACTOR; DNA-REPLICATION; BALF2 PROMOTER; BZLF1 PROTEIN; VIRAL GENOME; HUMAN-CELLS; EARLY GENE
ISSN (print) / ISBN 1553-7366
e-ISSN 1553-7374
Journal PLoS Pathogens
Quellenangaben Volume: 6, Issue: 9, Pages: e1001114 Article Number: , Supplement: ,
Publisher Public Library of Science (PLoS)
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Research Unit Gene Vector (AGV)
Institute of Human Genetics (IHG)