Enhancer loops appear stable during development and are associated with paused polymerase

A high-resolution map of enhancer three-dimensional contacts during Drosophila embryogenesis shows that although local regulatory interactions are frequent, long-range interactions are also very common; unexpectedly, most interactions appear unchanged between tissues and across development and are formed prior to gene expression, indicating that transcription initiates from preformed enhancer–promoter loops, which are associated with paused polymerase. Enhancer activity during embryogenesis Two papers in this issue of Nature examine the role of developmental enhancers in Drosophila melanogaster , an ideal model for the purpose, as it takes just 18 hours from egg laying to completion of embryogenesis and involves marked changes in transcription linked to changes in enhancer activity. Evgeny Kvon et al . systematically assayed the activity of more than 7,000 candidate enhancers. Nearly half of the tested genomic fragments are active in the embryo and display dynamic spatial patterns during development. Enhancer activity is matched to expression patterns of putative target genes and predictive cis -regulatory motifs are identified. Yad Ghavi-Helm et al . present a high-resolution map of enhancer three-dimensional contacts. They find that although there are many local regulatory interactions, long-range interactions are more common. Surprisingly, most interactions appear unchanged between tissues and across development. Thus, transcription initiates from preformed enhancer–promoter loops through release of paused polymerase. The study also implies that the general topology governing enhancer contacts is conserved from flies to humans. Developmental enhancers initiate transcription and are fundamental to our understanding of developmental networks, evolution and disease. Despite their importance, the properties governing enhancer–promoter interactions and their dynamics during embryogenesis remain unclear. At the β-globin locus, enhancer–promoter interactions appear dynamic and cell-type specific 1 , 2 , whereas at the HoxD locus they are stable and ubiquitous, being present in tissues where the target genes are not expressed 3 , 4 . The extent to which preformed enhancer–promoter conformations exist at other, more typical, loci and how transcription is eventually triggered is unclear. Here we generated a high-resolution map of enhancer three-dimensional contacts during Drosophila embryogenesis, covering two developmental stages and tissue contexts, at unpreced