CpG-Methylation Regulates a Class of Epstein-Barr Virus Promoters

PLoS Pathogens

Ulrich Rothbauer¹  Christine Göbel²  Markus Kalla²  Anne Schmeinck²  Wolfgang Hammerschmidt²  Martin Bergbauer²  Sebastian Eck³  Anna Benet-Pagès³  Tim M. Strom³ 

[1] Biocenter at the Department of Biology II, Ludwig-Maximilians University Munich, Martinsried, Germany;Department of Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany;Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

关键词: DNA methylation;    Sequence motif analysis;    Immunoprecipitation;    Raji cells;    DNA-binding proteins;    Viral genes;    Chromatin;    Plasmid construction;   

DOI  :  10.1371/journal.ppat.1001114

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY