Super-enhancer

In genetics, a super-enhancer is a region of the mammalian genome comprising multiple enhancers that is collectively bound by an array of transcription factor proteins to drive transcription of genes involved in cell identity. Because super-enhancers are frequently identified near genes important for controlling and defining cell identity, they may thus be used to quickly identify key nodes regulating cell identity.

Enhancers have several quantifiable traits that have a range of values, and these traits are generally elevated at super-enhancers. Super-enhancers are bound by higher levels of transcription-regulating proteins and are associated with genes that are more highly expressed. Expression of genes associated with super-enhancers is particularly sensitive to perturbations, which may facilitate cell state transitions or explain sensitivity of super-enhancer—associated genes to small molecules that target transcription.

The regulation of transcription by enhancers has been studied since the 1980s. Large or multi-component transcription regulators with a range of mechanistic properties, including locus control regions, clustered open regulatory elements, and transcription initiation platforms, were observed shortly thereafter. More recent research has suggested that these different categories of regulatory elements may represent subtypes of super-enhancer.

In 2013, two labs identified large enhancers near several genes especially important for establishing cell identities. While Richard A. Young and colleagues identified super-enhancers, Francis Collins and colleagues identified stretch enhancers. Both super-enhancers and stretch enhancers are clusters of enhancers that control cell-specific genes and may be largely synonymous.

As currently defined, the term “super-enhancer” was introduced by Young’s lab to describe regions identified in mouse embryonic stem cells (ESCs). These particularly large, potent enhancer regions were found to control the genes that establish the embryonic stem cell identity, including Oct-4, Sox2, Nanog, Klf4, and Esrrb. Perturbation of the super-enhancers associated with these genes showed a range of effects on their target genes’ expression. Super-enhancers have been since identified near cell identity-regulators in a range of mouse and human tissues.

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