title: Enhancer loops appear stable during development and are associated with paused polymerase.
abstract: 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, whereas at the HoxD locus they are stable and ubiquitous, being present in tissues where the target genes are not expressed. 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 unprecedented resolution. Although local regulatory interactions are common, long-range interactions are highly prevalent within the compact Drosophila genome. Each enhancer contacts multiple enhancers, and promoters with similar expression, suggesting a role in their co-regulation. Notably, most interactions appear unchanged between tissue context and across development, arising before gene activation, and are frequently associated with paused RNA polymerase. Our results indicate that the general topology governing enhancer contacts is conserved from flies to humans and suggest that transcription initiates from preformed enhancer-promoter loops through release of paused polymerase.
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, D-69117 Heidelberg, Germany.
authors.forename: Yad
authors.initials: Y
authors.lastname: Ghavi-Helm
authors.affiliation: 1] European Molecular Biology Laboratory, Genome Biology Unit, D-69117 Heidelberg, Germany [2].
authors.forename: Felix A
authors.initials: FA
authors.lastname: Klein
authors.affiliation: 1] European Molecular Biology Laboratory, Genome Biology Unit, D-69117 Heidelberg, Germany [2].
authors.forename: Tibor
authors.initials: T
authors.lastname: Pakozdi
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, D-69117 Heidelberg, Germany.
authors.forename: Lucia
authors.initials: L
authors.lastname: Ciglar
authors.affiliation: Swiss Federal Institute of Technology, School of Life Sciences, CH-1015 Lausanne, Switzerland.
authors.forename: Daan
authors.initials: D
authors.lastname: Noordermeer
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, D-69117 Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Huber
authors.affiliation: European Molecular Biology Laboratory, Genome Biology Unit, D-69117 Heidelberg, Germany.
authors.forename: Eileen E M
authors.initials: EE
authors.lastname: Furlong
mesh_terms: D000818:Animals; D001665:Binding Sites; D059006:Chromosomes, Insect / Q000235:genetics / Q000378:metabolism; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000196:embryology / Q000201:enzymology* / Q000235:genetics*; D047108:Embryonic Development / Q000235:genetics*; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics; D049750:Genome, Insect / Q000235:genetics; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics*; D061785:Transcription Initiation, Genetic; D015533:Transcriptional Activation
chemical_list: D012321:DNA-Directed RNA Polymerases