Topological regulation of the estrogen transcriptional response by ZATT-mediated inhibition of TOP2B activity [ICE-Seq]

Human type-II topoisomerases, TOP2A and TOP2B, remove DNA supercoiling associated with transcription, have been shown to affect several gene-expression programs, and have been correlatively linked to 3D genome architecture, although through a still poorly understood function. To study in depth the regulatory roles of TOP2 paralogs, we have used the well-characterized cellular response to estrogen as a model of acute transcriptional induction involving a rewiring of genome organization. We find that, as expected for a topoisomerase, TOP2A facilitates transcription. TOP2B, however, limits the expression of estrogen responsive genes under basal non-induced conditions, while, in response to estrogen treatment, its activity is locally downregulated to allow an accumulation of DNA supercoiling, and to favor the necessary regulatory chromatin contacts. Furthermore, this estrogen-mediated inhibition of TOP2B function requires estrogen receptor α (ERα), a non-catalytic function of TOP2A, and the action of the atypical SUMO-ligase ZATT. This mechanism of topological transcriptional-control may be shared by additional gene-expression circuits, in particular those involving a rewiring of genome organization, and highlights the relevance of DNA supercoiling and topoisomerases as central actors of genome dynamics.