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Large distances separate coregulated genes in living Drosophila embryos

Significance The prevailing model of gene activation is the looping of a distal enhancer to its target promoter, although it remains uncertain whether enhancers must come into direct contact. Recent studies suggest that clusters of RNA polymerase II are recruited to active genes, raising the possibility that enhancers cannot get too close to their target promoters due to molecular crowding. Here, we use live imaging methods to visualize genes that are simultaneously regulated by a single enhancer both in cis and in trans. We present evidence that these coregulated genes are separated by a substantial distance—at least 100–200 nm—during transcription. These observations challenge the textbook view of enhancer function and raise the possibility of an action-at-a-distance model for gene expression. Transcriptional enhancers are short segments of DNA that switch genes on and off in response to a variety of cellular signals. Many enhancers map quite far from their target genes, on the order of tens or even hundreds of kilobases. There is extensive evidence that remote enhancers are brought into proximity with their target promoters via long-range looping interactions. However, the exact physical distances of these enhancer–promoter interactions remain uncertain. Here, we employ high-resolution imaging of living Drosophila embryos to visualize the distances separating linked genes that are coregulated by a shared enhancer. Cotransvection assays (linked genes on separate homologs) suggest a surprisingly large distance during transcriptional activity: at least 100–200 nm. Similar distances were observed when a shared enhancer was placed into close proximity with linked reporter genes in cis. These observations are consistent with the occurrence of “transcription hubs,” whereby clusters (or condensates) of multiple RNA polymerase II complexes and associated cofactors are periodically recruited to active promoters. The dynamics of this process might be responsible for rapid fluctuations in the distances separating the transcription of coregulated reporter genes during transvection. We propose that enhancer-promoter communication depends on a combination of classical looping and linking models.