DNA methylation on island shores

US researchers led by one of the scientists who discovered the role of aberrant DNA methylation in human cancer have found that this type of epigenetic modification occurs more often in the ‘shores’ of CpG islands than within the islands themselves.

A team from Johns Hopkins University School of Medicine led by Andrew Feinberg, who along with Bert Vogelstein discovered the role of DNA methylation in human cancer in 1983, took a genome-wide search of DNA methylation sites.

They found to their surprise that about 76 per cent of methylation sites occur a short distance away from CpG islands, with only six per cent found within the islands themselves.

CpG islands are areas on the genome rich in the nucleotides cytosine and guanine. They usually occur close to the promoter or ‘start’ regions of genes – in humans, they are found in or near about 70 per cent of gene promoters.

DNA methylation is an epigenetic modification that affects gene expression and is implicated in many cancers.

The team used a technique called comprehensive high-throughput array-based relative methylation (CHARM) analysis to search DNA methylation on a genome-wide scale in 13 colorectal cancers.

For each sample, the researchers analysed about 4.6 million CpG sites using a custom-designed microarray that was ‘agnostic’ to preconceptions about DNA methylation, including location relative to genes and CpG content.

What they found was that most tissue-specific DNA methylation occurs in areas up to 2000 base pairs distant from CpG islands. They have named these new sites CpG island shores.

Interestingly, in colon cancers they found subtle difference between hypo- and hypermethylation in the regions that were altered. Hypermethylated sites were much more likely to include CpG islands than hypomethylated sites, which were more distant.

They also found that there was a distinct overlap in methylation sites in colon cancer and in normal tissue, finding that epigenetic changes in cancer involve the same areas as epigenetic changes in normal tissue. This, they say, has important implications for projects such as the Cancer Genome Atlas.

The study is published online in advance of publication in Nature Genetics.