Mechanisms of Enhancer Action

Abstract

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.