Extraordinary Cancer Epigenomics: Thinking Outside the Classical Coding and Promoter Box

The advent of functional genomics powered by high-throughput sequencing has given us a new appreciation of the genomic sequences that lie outside the canonical promoter-coding sequence box. These regions harbor distant regulatory elements, enhancers, super-enhancers, insulators, alternative promoters, and sequences that transcribe as noncoding RNAs (ncRNAs) such as miRNAs and long ncRNAs. These functional genomics studies have also enabled a clearer understanding of the role of the 3D structure of the genome in epigenetic regulation. Here we review the impact that epigenetic changes, and specifically DNA methylation, have on these extraordinary sequences in driving cancer progression.