The enhancers comprising super-enhancers share the functions of enhancers, including binding transcription factor proteins, looping to target genes, and activating transcription. Three notable traits of enhancers comprising super-enhancers are their clustering in genomic proximity, their exceptional signal of transcription-regulating proteins, and their high frequency of physical interaction with each other. Perturbing the DNA of enhancers comprising super-enhancers showed a range of effects on the expression of cell identity genes, suggesting a complex relationship between the constituent enhancers. Super-enhancers separated by tens of megabases cluster in three-dimensions inside the nucleus of mouse embryonic stem cells.
High levels of many transcription factors and co-factors are seen at super-enhancers (e.g., CDK7, BRD4, and Mediator).
This high concentration of transcription-regulating proteins suggests why their target genes tend to be more highly expressed than other classes of genes. However, housekeeping genes tend to be more highly expressed than super-enhancer—associated genes.
Super-enhancers may have evolved at key cell identity genes to render the transcription of these genes responsive to an array of external cues. The enhancers comprising a super-enhancer can each be responsive to different signals, which allows the transcription of a single gene to be regulated by multiple signaling pathways. Pathways seen to regulate their target genes using super-enhancers include Wnt, TGFb, LIF, BDNF, and NOTCH. The constituent enhancers of super-enhancers physically interact with each other and their target genes over a long range sequence-wise.
Super-enhancers that control the expression of major cell surface receptors with a crucial role in the function of a given cell lineage have also been defined. This is notably the case for B-lymphocytes, the survival, the activation and the differentiation of which rely on the expression of membrane-form immunoglobulins (Ig). The Ig heavy chain locus super-enhancer is a very large (25kb) cis-regulatory region, including multiple enhancers and controlling several major modifications of the locus (notably somatic hypermutation, class-switch recombination and locus suicide recombination).