DNA methylation at enhancer regions: Novel avenues for epigenetic biomarker development

Biomarkers are molecules or features which can provide clinically-relevant information about a particular disease state, thus providing useful tools for oncologists. Recently, a number of studies have demonstrated that DNA methylation holds great promise as a novel source of cancer biomarkers. Although promoter regions have been the focus of most investigations thus far, mounting evidence demonstrates that enhancer sequences also undergo extensive differential methylation in cancer cells. Moreover, enhancer methylation correlates with target gene expression better than promoter methylation, providing unexplored strategies for biomarker development. Here, we review important considerations associated with the clinical analysis of DNA methylation at distal regulatory regions. Notably, we highlight emerging literature addressing the methylation status of enhancers in development and cancer, and subsequently discuss how enhancer methylation can be exploited to guide disease management. While acknowledging current limitations, we propose that the methylation state of enhancer regions has the potential to headline the next generation of epigenetic biomarkers.