Mechanisms of Enhancer Action


Genomic studies have revealed a large number of distantly acting regulatory DNA regions (enhancers) activating transcription both in bacteria and in eukaryotes. Enhancers contain multiple specific binding sites for activator proteins that can locally disturb chromatin structure after binding to DNA and activate transcription initiated from enhancer targets (promoters) localised at variable distances from the enhancer. Typically, interactions between enhancer‐ and promoter‐bound proteins involve chromatin looping of intervening stretches of DNA organised in chromatin. These dynamic regulatory chromatin loops of different size and stability operate both in bacteria and in higher organisms where they form extensive and complex three‐dimensional networks that largely define gene expression patterns and identity of eukaryotic cells. Misalignment of these networks results in development of numerous human diseases including cancer.

Key Concepts

  • Enhancers are regulatory DNA sequences that regulate transcription both in bacteria and in higher organisms.
  • Enhancers are activated after binding of activator proteins to their specific binding sites localised within the enhancers.
  • Enhancers activate their targets (promoters) over variable distances.
  • An enhancer can work on multiple promoters and a promoter can be activated by multiple enhancers.
  • As a result, there is a dynamic regulatory network formed by regulatory chromatin loops of different size and stability.
  • Promoter activation involves interaction between proteins bound at the enhancers and promoters.
  • Enhancer–promoter interaction is accompanied by looping of intervening chromatin.
  • Gene activation involves a conformational change in promoter‐bound proteins or their covalent modification.

Keywords: distant regulation; enhancer; promoter; active chromatin; enhancer‐binding proteins; DNA looping; enhancer–promoter communication; transcription; poised chromatin

Figure 1. Mechanism of action of bacterial σ54‐dependent and eukaryotic enhancers. (a) Bacterial enhancers. Before transcriptional activation, bacterial enhancer‐binding proteins (bEBPs) are bound to the enhancer and do not communicate with the promoter containing bound, but inactive RNA polymerase forming a closed complex. After induction, phosphorylated bEBP oligomerises and can interact with the inactive RNA polymerase. Enhancer–promoter communication leads to looping of the intervening DNA and ATP hydrolysis‐dependent formation of the open, functionally active initiation complex at the promoter. After formation of the active initiation complex, the DNA loop is opened. (b) Eukaryotic enhancers. During differentiation, inactive enhancers are primed with pioneering transcription factors and marked by histone variants H2A.Z and H3.3. Early during development many promoters that become active later in development are pre‐marked by the histone modification and are poised. During enhancer activation, a set of specific transcription factors binds to the enhancer, attracting histone modifying enzymes such as histone acetyltransferases and inducing enhancer–promoter communication, chromatin looping and promoter activation. Histone modifications activating and inactivating enhancers are shown in green and red, respectively.


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Further Reading

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Vermunt MW, Zhang D and Blobel GA (2019) The interdependence of gene‐regulatory elements and the 3D genome. The Journal of Cell Biology 218: 12–26.

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Nizovtseva, Ekaterina V, and Studitsky, Vasily M(Jun 2019) Mechanisms of Enhancer Action. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0028532]