What makes a cell become a cancerous? We’d all love to know that, right? Well, new research has gotten a little bit closer to figuring out key epigenetic differences between cancer and normal genomes. It turns out that the DNA methylation patterns of these cells differ drastically, no surprise there, but it’s the genomic context that makes all the difference.
Researchers in Peter Laird’s group at USC along with Dutch scientists used whole-genome bisulfite sequencing to profile and compare the methylation patterns of DNA in a colorectal tumor and nearby normal tissue. Overall, DNA methylation was higher in CpG islands (CGIs) in the tumor, but lower elsewhere. Here are several additional insights from the data-rich paper:
- 5,163 elements were methylated in tumor, but not normal, cells (“methylation-prone”). 21,134 elements weren’t methylated in either cell type (“methylation-resistant”). 662 elements were methylated in normal, but not tumor, tissue (“methylation-loss”).
- Methylation-resistant elements were enriched for transcription-factor binding sites.
- As expected, gain of methylation corresponded well with silencing in tumors, and loss of methylation corresponded with increased expression.
- In many methylation-loss cases, methylation disappeared from transcription-factor binding sites in CGIs, so perhaps these areas are enhancers or un-annotated promoters.
Looking closer, the researchers discovered small, focal areas of hypermethylation inside of tumor partially methylated domains (PMDs), which are long stretches of hypomethylation. Here’s some other fun facts about PMDs:
- Colorectal tumor PMDs corresponded well with nuclear-lamina-associated domains (LADs; involved in developmental regulation of silencing) in fibroblast cells, though some boundaries were not the same. The researchers aren’t sure yet whether these seemingly cell-type-specific boundaries are normal or whether they’re a mark of cancer.
- Looking at data on fibroblast cell PMDs, the researchers found that H3K4me3 (associated with promoters) is enriched at PMD boundaries, but not within the PMDs. H3K9me3 (associated with heterochromatin) is enriched deep within PMDs. The PMD boundaries also were in late-replication areas.
The researchers say that more studies comparing immortalized cells, which have PMDs but not the focal hypermethylation pattern, with cancer cells, which have PMDs and focal hypermethylation, may provide even more info on how cells become cancerous.
Find out more about the DNA methylation differences of cancer tissues at Nature Genetics, November 2011.
**Grab every bit of methylated DNA in your sample with EMD Millipore’s CpG MethylQuest DNA Isolation Kit.