Potential role of intervening DNA between enhancers and promoters, and factors that associate with it, in enhancer function. An enhancer and a promoter within a gene locus (top left) are both bound by sequence-specific factors, which in turn serve to recruit a factor or complex that then associates with chromatin throughout the locus (bottom left). We depict several potential mechanisms that might then ensue: (1) factors bound between the enhancer and promoter serve to organize the intervening chromatin in order to bring the two elements together spatially; (2) factors extending from the enhancer to the promoter along the intervening chromatin serve as the primary signal for gene activation, with no necessary role for enhancer-promoter juxtaposition; (3) factors associating with the intervening chromatin organize the locus to bring both enhancer and promoter to a transcription factory and accomplish gene activation. Conceivably, enhancer-promoter juxtaposition at transcription factories may be an event secondary to gene activation, as in (2).

Potential mechanisms underlying distal enhancer-promoter colocalization. A. The “traditional” view of enhancer-promoter interactions, in which proteins bound to the enhancer (ENH) and other proteins bound to the promoter (PRO) directly interact with each other to facilitate transcriptional activation, whether by recruitment of RNA polymerase II (as shown), stimulation of RNA polymerase II elongation (as demonstrated for the β-globin LCR), or another mechanism. Blue circles represent nucleosomes; based on the best available evidence, we have depicted the majority of intervening sequence between the enhancer and promoter as condensed to the 30 nm fiber, although higher-order chromatin structure is not well understood and so compaction may be more extensive than this. B. Enhancer-promoter colocalization by association with RNA polymerase II transcription “factories”. In this model, factors bound to both enhancer and promoter independently recruit RNA polymerase II; in a nuclear environment consisting of transcription “factories”, however, this amounts to enhancer and promoter colocalizing to the same “factory”. The green circles represent as-yet undefined, non-Pol II proteins presumed to be present in transcription factories. C. Enhancer and promoter interactions with specific transcription factories. In this model, different genes associate with different kinds of transcription factories. Such specific association is presumably mediated by some common factor or complex recruited to both the enhancer and the promoter (denoted by violet or green circles, respectively), and would be expected to underlie specific interchromosomal interactions.