Scientists studying how human chemistry can permanently turn off genes have typically focused on small islands of DNA believed to contain most of the chemical alterations involved in those switches. But after an comprehensive search of DNA methylation sites across the human genome in normal and cancer cells, scientists from Johns Hopkins University School of Medicine have found that the vast majority of the sites aren't grouped in those islands at all, but on nearby regions that they have named “shores” instead.
The long-time focus in methylation has been CpG islands, regions of the genome rich in the DNA building-block molecules cytosine and guanine. These islands tend to occur near the “start” signal of a protein-coding gene, a place with the potential to affect whether that gene is expressed or not and to what extent. In this research, the investigators performed their survey in human brain, liver, and spleen tissues obtained from five autopsies. They discovered 16,379 methylated regions using a new method that searches all DNA, not just CpG islands.
“Our study suggests that the real jackpot for methylation isn’t where we have all been looking, but in these shores located just nearby,” says Andrew Feinberg, M.D., M.P.H., professor of medicine at the Johns Hopkins University School of Medicine.
The team was surprised to discover that about 76% of the genome's methylated sites occur a short distance away from the islands, between 200 and 2,000 kilobases away. In contrast, only 6% of methylated sites were situated inside CpG islands. Because of the newly discovered sites’ proximity to the islands, the researchers named them CpG shores.
Next, the colleagues searched for new methylated areas in colon tumors as well as normal colon tissue removed from 13 different cancer patients. The researchers identified 2,707 regions in both CpG islands and shores that were either more or less methylated between the two tissue types. Previous studies by other research groups looking only at CpG islands have suggested that the DNA in cancer cells tends to be more methylated compared to normal, healthy cells. However, comparing the tumor and healthy colon cells’ entire genomes, including CpG islands as well as shores, the team found that cancer cells had a roughly equal number of more-methylated and less-methylated sites than the normal cells.
When the researchers looked at where these differently methylated sites were located in the cancer cells, they found that these regions matched up with many of the methylated areas they'd located in the normal brain, liver, and spleen tissues they had examined.
“This suggests that the epigenetic changes we see in cancer are leading cells to look and behave like other cells they’re not at all supposed to be like,” Dr. Feinberg says. “For example, colon cells that become cancerous might start to act like brain, liver, or spleen cells. They’re losing the characteristics they should have and taking on those of other tissues.”
Dr. Feinberg and his colleagues suggest in the study, published online on January 18 in Nature Genetics, that their newly developed map of where these methylation sites differ in colon cancer and healthy tissue may eventually help researchers develop treatments for cancer by restoring normal methylation patterns or by targeting the gene pathways they have identified in this study.
The study is published in the January 18 online edition of Nature Genetics.