Clusters of active enhancers (super-enhancers) are generated near oncogenes in cancer cells.
Major finding: Clusters of active enhancers (super-enhancers) are generated near oncogenes in cancer cells.
Mechanism: Translocations, amplifications, and transcription factor overexpression create super-enhancers.
Impact: Candidate driver genes might be identified by mapping super-enhancers in different cancer types.
Enhancers are DNA regulatory elements that control the expression of associated distal genes. Clusters of active enhancers bound by master transcription factors and the Mediator complex, termed super-enhancers, have been found to drive high-level expression of genes that control cell identity. Hnisz and colleagues found that 11 transcription factors, as well as coactivators, chromatin regulators, and RNA polymerase II, were highly enriched at embryonic stem cell super-enhancers compared with regular enhancers, providing an explanation for the high expression levels of super-enhancer–associated genes. Using histone H3 lysine 27 (H3K27ac) acetylation as a surrogate super-enhancer mark, a catalog of super-enhancers was generated for 86 different human cell and tissue types that revealed that the majority of super-enhancers and super-enhancer–associated genes are cell type specific. This approach has the potential to identify key determinants of cell fate, given that highly expressed transcription factors encoded by super-enhancer–associated genes may themselves act as master transcription factors for that particular cell type. Risk alleles identified in genome-wide association studies were also enriched in super-enhancers of disease-associated cell types, pointing to a common theme of cell identity gene deregulation in pathogenesis. Interestingly, when compared with their normal counterparts, cancer cells were found to acquire super-enhancers at known oncogenes, raising the possibility that other super-enhancer–associated genes could be candidate oncogenic drivers. These super-enhancers were tumor type specific, even if they formed in the same gene locus, and could arise from translocations that placed super-enhancers near genes, amplifications of regions containing super-enhancers, or overexpression of master lineage-specific transcription factors that bind super-enhancers. As more than one third of genes that acquired super-enhancers in cancer cells have functions that have been associated with one of the hallmarks of cancer, these findings suggest that generation of super-enhancers is a common tumorigenic mechanism.