Abstract
DNA methylation at CpG motifs provides an epigenetic route to regulate gene expression. In general, an inverse correlation between DNA hypermethylation at CpG motifs and gene expression is observed. Epstein Barr-virus (EBV) infects people and the EBV genome resides in the nucleus where either its replication cycle initiates or it enters a long-term latency state where the viral genome becomes hypermethylated at CpG motifs. Viral gene expression shows a largely inverse correlation with DNA hypermethylation. DNA methylation occurs through the action of DNA methyl transferase enzymes: writer DNA methyl transferases add methyl groups to specific regions of unmethylated DNA; maintenance DNA methyl transferases reproduce the pattern of DNA methylation during genome replication. The impact of DNA methylation is achieved through the association of various proteins specifically with methylated DNA and their influence on gene regulation. DNA methylation can be changed through altering DNA methyl transferase activity or through the action of enzymes that further modify methylated CpG motifs. Azacytidine prodrugs that are incorporated into CpG motifs during DNA replication are recognized by DNA methyl transferases and block their function resulting in hypomethylation of DNA. EBV-associated cancers have hypermethylated viral genomes and many carcinomas also have highly hypermethylated cellular genomes. Decitabine, a member of the azacytidine prodrug family, reactivates viral gene expression and promotes the recognition of lymphoma cells by virus-specific cytotoxic T-cells. For EBV-associated cancers, the impact of decitabine on the cellular genome and the prospect of combining decitabine with other therapeutic approaches is currently unknown but exciting.
Highlights
DNA methylation at the 5-position of the cytosine ring of CpG motifs in DNA provides an epigenetic route to regulate gene expression (Klose and Bird, 2006)
Maintenance DNA methyl transferases enzymes are responsible for maintaining the DNA methylation pattern in daughter cells by adding methyl groups to the newly replicated strand of the hemi-methylated CpG motifs that are synthesized during genome replication (Klose and Bird, 2006)
The pressing question is whether decitabine treatment could provide a relevant clinical approach to treat Epstein Barr-virus (EBV)-associated lymphomas and carcinomas? Decitabine has a proven potential to drive hypomethylation of the viral genome and to prime EBVassociated lymphoma cells to re-express immunogenic viral genes (Dalton et al, 2020)
Summary
DNA methylation at the 5-position of the cytosine ring of CpG motifs in DNA provides an epigenetic route to regulate gene expression (Klose and Bird, 2006). Extensive DNA methylation is generally associated with mammalian genes that are not expressed (Suzuki and Bird, 2008), with some cell-type specific genes showing a consistent pattern of DNA methylation found in key regions of the genome (Schmidl et al, 2009)
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