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

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.