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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE236411 | GEO | 2025/12/31

REPOSITORIES: GEO

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

Project description: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.

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Project description:Aberrant activity of type II topoisomerases (TOP2) often causes blocked double-strand breaks (DSBs), whose inefficient repair can seriously compromise genomic stability. One of the two TOP2 paralogs encoded in vertebrates is TOP2B, which has been linked to essential processes such as transcription or genome organization. Few TOP2B genome-wide maps have been profiled, and a comprehensive study of the mechanisms involved in TOP2B-DNA binding is still lacking. Here, we conduct an in silico approach for the prediction of TOP2B binding sites using publicly available sequencing data. We achieve highly accurate predictions and find that open chromatin and architectural factors are the most informative features. We also validate our predictions on experimental data and generate predicted TOP2B tracks that mirror experimental ones with high precision.

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