Regulatory Domains and Their Mechanisms

The concept of gene regulation is being refined as our understanding of the role of enhancer elements grows. Although described more than 30 years ago, the mechanisms through which these cis-regulating elements operate remain under debate. With the recognition that most of the human genetic variation contributing to common disease risk lies outside of genes and probably in enhancers, unraveling these mechanisms becomes ever more important. Originally, a popular view was to consider regulatory elements as an entry site for the transcription machinery that could scan the intervening chromatin until the cognate core promoter was located. Now, the most prominent model for distal enhancer-promoter interaction involves direct enhancer/promoter contacts with a looping out of intervening chromatin. However, a rising awareness of the importance of chromatin architecture and organization forces us to consider enhancer-promoter communication in light of the polymer folding properties of chromatin. Here, we discuss how three-dimensional chromatin folding, topological domains, and the constrained motion, plasticity, and accessibility of chromatin could offer a structural basis for regulatory domains that greatly enhances the probability of enhancer-promoter and transcription factor-promoter interactions and gene activation.