Ligand mediated interactions between ER alpha enhancers on chromosome 21 results in the formation of a distributed estradiol super enhancer.

by Lu Yang

Institution: University of California San Diego
Year: 2017
Keywords: Biology; CRISPR; Enhancer; Estrogen; FISH; Genetics
Posted: 02/01/2018
Record ID: 2175495
Full text PDF: http://www.escholarship.org/uc/item/5g38r02z


Discovery of transferable distal genetic elements capable of activating gene transcription was a milestone in the study of transcriptional control. These genetic elements were termed enhancers because of their ability to enhance proximal coding gene transcription. Since then, it was believed that the activation potential of enhancers is entirely intrinsic. However, most prior studies of enhancer elements have removed them from their native genomic context, transplanting them onto plasmids or artificial chromosomes, thereby removing any potential effects of other elements in the genome. We sought to ask the question of whether the strongest E2 regulated enhancers on human chromosome 21 might interact, even when located on opposite ends of the chromosome q arm. These interactions play a functional role in allowing all interacting enhancers to have synergistically high levels of robustness. We have found that a cohort of the most highly active first tier ER bound enhancers on chromosome 21, distributed across a linear distance of over 30 mega-bases, exhibit induced proximity when treated with the ligand agonist estradiol-17 (E2). Using CRISPR-Cas9 technology to delete some of these enhancers, we found, these enhancers seem to confer additional robustness onto other interacting enhancers. We believe that this occurs due to the physical proximity between first tier enhancers gained in response to E2, and that these interactions are dependent upon eRNA and a host of protein factors. These individual first tier enhancers in effect form a previously unappreciated spatially distributed super-enhancer network. These interaction events reflect physical constraints placed upon chromosome 21 imposed by a very large heterochromatic B compartment, which seems to predominantly localize to the surface of the nucleolus arising from the ribosomal DNA repeat rich p-arm of the acrocentric chromosome 21. The euchromatin A compartments on either side of the B compartment are thus allowed to interact dynamically. These sorts of dynamic interactions between regions of the chromosome constitute, in part, the overall structure of the chromosome. Therefore, the robustness of individual enhancers in a chromosome cannot be disentangled from the contributions of all interacting enhancers and the subnuclear structures in which these interactions can occur.