How Understanding DNA Methylation May Help Treat Lymphoma More Effectively

摘要

First reported in 1949, methylcytosine in DNA sequences has become a central focus as an epigenetic mechanism of gene regulation in normal, chronic disease, and neoplastic disease processes. Methylcytosine is created post-replication by the addition of a methyl group to the 5 position of the cytosine ring when a cytosine is followed by a guanine (CpG) in sequence. The addition is made by DNA methyltransferases (DNMTs) using the methyl donor s-adenosyl methionine. DNMT1 is responsible for maintenancemethylation by which parental strand methylation patterns are copied onto daughter strand CpGs post-replication. DNMT3a is responsible for placing methylation marks on CpGs under conditions of dynamic epigenetic change. Mutations of both proteins have been associated with alterations of both global genomic methylation and gene promoter-specific methylation associated with cancer. Across mammalian genomes, CpG dinucleotides are relatively rare sequential base pairs. Sporadically, CpG may be found in highdensity in regions called CpG islands that are frequently located in association with the 5' control regions of genes. Hypermethylation of these islands was originally thought to result in persistent silencing of the associated gene. New work has demonstrated, however, that chromatin marks on histones are responsible for the active silencing of the gene, which can often be expressed even when methylated. These hypermethylated genes will revert to a silenced state in relatively short order when the signal for the histone changes recedes.1 Recently, a third concept of CpGs has emerged. The CpGs residing in the lower density regions near CpG islands are considered to reside on the "shores" and "shelves" of those islands and appear to play a significant role in cell development and stem cell function. The first reported examination of DNA methylation in canine cancer was in 2003 when lymphomas were shown to be characterized by the same global loss of DNA methylation seen in human lymphomas.2 Subsequently, the often hypermethylated FHIT gene was studied in canine lymphoma cell lines and found to be aberrantly expressed, but hypermethylation could not be documented to be the cause.3 Conversely, the DLC1 gene was shown to be significantly hypermethylated in canine lymphoma patient samples, but no effect on the expression of the gene could be identified.4 Put most simply, epigenetic changes like DNA methylation are the mechanism by which cells establish persistent and stable phenotype while sharing a common genotype across all cells. Certain sets of genes in each cell are mostly permanently turned on or off to limit the set of proteins that are expressed. These mechanisms become disrupted in the course of carcinogenesis, changing the gene sets available to cancer cells and resulting in significant genetic and epigenetic plasticity.