Enhancer cooperativity in the folded genome

Transcriptional regulation involves the binding of thousands of transcription factors (TFs) to hundreds of thousands of enhancers and promoters. How do the collective activities of these proteins and cis-regulatory elements achieve precise and dynamic gene regulation? At an individual enhancer, TFs can interact to affect each other's binding and the recruitment of different co-factors, resulting in cooperative outputs. More recently, new types of cooperative behaviour between enhancers have been discovered. In this review, we consider whether some of the same principles could contribute to both TF and enhancer cooperativity, focusing specifically on positive cooperativity (or synergy) and the role of 3D chromatin organisation.