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.
Highlights
The methylation of cytosines in CpG dinucleotides in mammalian DNA has long been associated with the regulation of transcription of that DNA
We have found previously that (i) Epstein-Barr virus (EBV) DNA is unmethylated upon infection, but becomes methylated over time by the host B cell, and (ii) the BZLF1-encoded protein, Zta, induces the viral lytic cycle, but it prefers binding sites that are CpGmethylated
Among them are genes essential for EBV’s lytic phase, which paradoxically depend on strictly CpGmethylated promoters for their Zta-induced expression
Summary
The methylation of cytosines in CpG dinucleotides in mammalian DNA has long been associated with the regulation of transcription of that DNA. The details of this regulation, are only being uncovered. An example in which expressed genes are repressed during differentiation is provided by murine embryonic stem cells induced to differentiate into neurons [2] In this example, 2.3% of analyzed promoters become hypermethylated following differentiation with the associated genes being transcriptionally repressed leading to a loss of pluripotency. These examples demonstrate that CpG methylation is strictly linked to epigenetic gene silencing but are difficult to dissect mechanistically in part because of the complexity of the cues for differentiation that underlie them
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