SuperEnhancers

Super-enhancers are large clusters of transcriptional enhancers that drive the high-level expression of genes governing cell identity. The term was introduced in 2013 by Whyte and colleagues, who observed that a subset of enhancer regions showed exceptionally high occupancy by the Mediator complex and elevated H3K27ac marks. By stitching nearby enhancer elements within a defined distance and ranking them by signal strength, these regions were distinguished from typical enhancers and labeled as super-enhancers.

Identification and properties. Most studies identify super-enhancers using ChIP-seq for Mediator, BRD4, or H3K27ac, followed by segment stitching and ranking. Regions at the top of the rank are designated super-enhancers. They tend to be larger, show dense occupancy by transcription factors and coactivators, and are strongly associated with genes that control cell fate and identity. They are thought to promote robust transcription, potentially through mechanisms such as cooperative enhancer activity and chromatin looping that facilitates promoter contact.

Biological and clinical relevance. Super-enhancers are implicated in development, differentiation, and disease. They often govern lineage-determining genes and can be particularly important in cancer, where oncogenes may be linked to super-enhancers. Because of their reliance on transcriptional machinery, they are showing up as therapeutic targets; inhibitors of BRD4 or other components of the transcriptional apparatus can preferentially affect super-enhancer–driven transcription. Nevertheless, the concept remains debated: not all clusters uniquely define essential genes, and the boundaries between super-enhancers and ordinary enhancers can be fluid. Functional validation and careful interpretation are important when applying this concept to biology and therapy.