Unexpected stability and complexity in transcriptional enhancers’ interactions
Enhancers find their targets long before they are activated
Long-distance action and complexity of enhancer interactions in fruit fly are comparable to those known from vertebrates
Contrary to what was thought, sequences of DNA called enhancers – which control a gene’s output – find their targets long before they are activated during embryonic development, scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, have found. Their study, published online today in Nature, also reveals that, surprisingly, the degree of complexity of enhancers’ interactions in the ‘simple’ fruit fly Drosophila is comparable to what is seen in vertebrates.
“As an embryo develops, there are huge changes in transcription, much of which drives developmental progression: genes are changing from on to off, and off to on – but the contacts between enhancers and their target genes remain largely unchanged,” says Eileen Furlong from EMBL, who led the work. “Enhancers regulate transcription, so it was really surprising that there are few changes in their interactions at a time when transcription is changing.”
To activate a gene, an enhancer has to come into contact with the portion of DNA at the start of the gene – its promoter. For enhancers that are located far away from their targets, the cell achieves this by looping the DNA around to bring about that contact. Yad Ghavi-Helm, a postdoctoral fellow in Furlong’s lab, found that, in developing fruit fly embryos, these DNA loops are formed, contact is established, and the cell’s gene-reading machinery is recruited, hours before the gene is expressed. The results indicate that the whole system is primed in advance, ready to spring to action when needed.
When they looked at all the enhancers that are known in Drosophila and mapped what genes they establish contacts with, the EMBL scientists discovered that these genetic regulators act across long distances in the genome, and in complex ways. Such a prevalence of long-distance action and such complex interactions were previously known to be widespread among vertebrates, but these findings show that they evolved much earlier.
For Furlong, Ghavi-Helm and colleagues, the study opens up a plethora of further questions: At what point in an embryo’s life do enhancer loops form? And how long after a gene has been switched off do the loops remain? If loop formation isn’t the trigger for gene activation, what is? What’s the exact role of the contacts they have found? And finally, a technically challenging question: unravelling if all an enhancer’s interactions are happening at the same time in the same cell.
The study was performed in collaboration with Wolfgang Huber’s lab at EMBL, which assisted with the raw data processing and normalisation.
Ghavi-Helm, Y., Klein, F.A., Pakozdi, T., Ciglar, L., Noordermeer, D., Huber, W. & Furlong, E.M. Enhancer loops appear stable during development and are associated with paused polymerase. Published online in Nature, 2 July 2014. DOI: 10.1038/nature13417.
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 specific1,2, while at the HoxD locus they are stable and ubiquitous, being present in tissues where the target genes are not expressed3,4. To what extent preformed enhancer-promoter conformations exist at other, more typical, loci and how transcription is triggered remains 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. Surprisingly, 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.
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