TOP2B modulates DNA supercoiling-driven chromatin contacts during transcriptional induction

Human type-II topoisomerases, TOP2A and TOP2B, resolve transcription-associated DNA supercoiling, thereby influencing gene-expression programs, and have been recently linked to 3D genome architecture through yet poorly understood mechanisms. Here, we investigate the regulatory roles of TOP2 paralogs using estrogen signaling, which triggers an acute transcriptional induction that involves extensive rewiring of genome organization, as a model system. Unexpectedly, we find that estrogen treatment strongly inhibits TOP2B catalytic activity —though not its binding— specifically at estrogen-responsive enhancers and promoters. This inhibition results in an accumulation of negative DNA supercoiling and promotes the formation of regulatory chromatin contacts. Estrogen-mediated inhibition of TOP2B activity depends on estrogen receptor a (ERa), a non-catalytic function of TOP2A, and, most importantly, the action of the atypical SUMO-ligase ZATT (Zinc finger protein Associated with TDP2 and TOP2), which directly inhibits TOP2 activity. This mechanism of transcriptional control, involving the fine-tuning of DNA supercoiling levels, highlights the role of DNA topoisomerases as central regulators of genome dynamics.