Regional Activation of the Cancer Genome by Long-Range Epigenetic Remodeling

Epigenetic gene deregulation in cancer commonly occurs through chromatin repression and promoter hypermethylation of tumor-associated genes. However, the mechanism underpinning epigenetic-based gene activation in carcinogenesis is still poorly understood. Here, we identify a mechanism of domain gene deregulation through coordinated long-range epigenetic activation (LREA) of regions that typically span 1 Mb and harbor key oncogenes, microRNAs, and cancer biomarker genes. Gene promoters within LREA domains are characterized by a gain of active chromatin marks and a loss of repressive marks. Notably, although promoter hypomethylation is uncommon, we show that extensive DNA hypermethylation of CpG islands or “CpG-island borders” is strongly related to cancer-specific gene activation or differential promoter usage. These findings have wide ramifications for cancer diagnosis, progression, and epigenetic-based gene therapies. ► We identify an epigenetic-based mechanism of regional cancer gene activation ► Long-range epigenetic activation affects multiple adjacent tumor-associated genes ► Regions are characterized by gain of active chromatin marks and loss of repressive marks ► Promoter hypermethylation relates to cancer gene activation and changes in promoter usage