We like having all the important things close by—a stash of chocolate, a latte, and the remote control. But sometimes important things are far away. Take enhancers, for example. Enhancers are often pretty far from the genes whose transcription they are “enhancing.” And now, it turns out that DNA methylation at these enhancers can affect the expression of far-flung genes more than nearby promoters—especially in cancer.
Most DNA methylation-cancer studies have focused on promoters, CpG islands, and sometimes a bit further out (e.g. CpG shores), but this crew was keen on going the distance. They knew that DNA methylation at enhancers was associated with gene function, at least in mice. They wanted to know whether that held true in human cells and whether that changed in cancer.
To figure this out, they developed a model of DNA methylation and gene expression using data for 58 human cell lines. The model, which focused on sequences near the transcription start sites, worked well. They then extended that model to sites within 1 Mb of the start or end of genes. Here’s some of what they found:
- Distal methylation sites that had an association with expression were in a particular class of enhancers. These enhancers bound to transcription factors depending on the DNA methylation state.
- Surprisingly, enhancers had gradual methylation levels in different cell types—it wasn’t all or nothing. This could produce gradients of expression in a wide range of tissues.
- And the big surprise? Enhancer methylation is more closely associated with gene expression alterations in cancer than promoter methylation is.
“Our study brings two important messages to the attention of the epigenetic community: available methylomic data are very useful for predicting enhancer-gene pairing, and in contrast to the remote relationships between promoter methylation and gene dysregulation in cancer, enhancer methylation is drastically altered in cancers and is closely related to altered expression profiles of cancer genes,” says Asaf Hellman, the leader of the study.
Read all the details at Genome Biology, March 2013.