Cohesin forms fountains at active enhancers inC. elegans

Abstract

AbstractTranscriptional enhancers must find their target genes both efficiently and specifically. Chromatin conformation capture revealed the critical function of three-dimensional chromosome segmentation by topologically associated domains (TADs) to limit the search space of enhancers for promoters in mammals. In nematodes, although more than 30’000 sequences with characteristic enhancer chromatin features have been identified, the autosomal genome is not segmented by TADs, raising the question of the mechanism directing enhancer-promoter specificity. Using high-resolution HiC, we show that enhancer loci correlate with 3D hairpin-like structures extending 10-50 kb from the enhancers, hereafter designated as fountains. Fountains are specific to active enhancers, accumulate the major somatic cohesin and disappear when the latter is cleavedin vivo. Fountains accumulate topological constraints and are enriched for topoisomerases and the negatively-supercoiled DNA binder psoralen. Short-term topoisomerase depletion leads to small-scale structural changes at the fountain tip. Functionally, fountain disappearance correlates with enhancer-proximal gene activation, suggesting fountains play a similar role as TADs and direct enhancer-promoter interactions, in particular for genes expressed in neurons. We directly observe this cell-type specific upregulation for theskn-1/Nrfgene in a pair of head neurons. Phenotypically, cohesin cleavage has a major impact on nematode movement and foraging attitudes, demonstrating that changes in neuronal gene expression impact nervous system function, reminiscent of pathologies caused by cohesin mutations in humans. Together, this study highlights a clear link between 3D genome organization at enhancers by cohesin, transcriptional gene regulation and animal behavior.