Fig. 1.

Organisation of active enhancers in cis. A Enhancers become activated by pioneer factors that increase chromatin accessibility, perhaps through histone displacement, allowing for binding of cell-specific TFs and cofactors. Cofactors such as P300 and MLL perform chromatin remodelling via acetylation or methylation of histone tails. TFs and cofactors recruit BRD4/Mediator and further transcriptional machinery to begin active transcription at the enhancer and the distal gene promoter. B Models of enhancer grammar include the rigid Enhanceosome model [88], in which TFs bind in a particular order and spacing; the Billboard model, in which TFs bind in a very flexible arrangement [90], and the TF Collective model, in which a full set of particular TFs is required for enhancer activation, but not all TFs must bind directly to the DNA and instead are recruited via protein–protein interactions [91]