The Semantics and Mechanisms of Enhancers and Promoters: “What Is True for E. coli Is True for the Elephant, Only More So”

Three fundamental classes of gene regulatory elements were identified in Escherichia coli in the 1960s: operators bound by repressor proteins, promoters bound by the basic transcription machinery, and enhancers bound by activator proteins. Promoters mediate constitutive gene expression, whereas operators and enhancers regulate expression in response to physiological conditions. As discovered in the 1980s, interactions between proteins associated with spatially separated elements can loop out the intervening DNA and regulate transcription. Eukaryotic gene regulation is mediated by the same three classes of genetic elements, but due to semantic confusion, it is often believed the eukaryotic enhancers activate transcription from long distances via enhancer–promoter loops. However, eukaryotic enhancers mediate only local changes in chromatin, and they stimulate transcription via directional and short-range interactions with the basic Pol II machinery at promoters. Enhancer action at a distance is mediated by loops between proximal and distal enhancers that bring activator proteins associated with distal enhancers in proximity to promoters. Thus, Jacques Monod's 1954 conjecture that “what is true for E. coli is true for the elephant, only more so” has proven correct.