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Mapping catalytically engaged TOP2B in neurons reveals the principles of topoisomerase action within the genome [fastGRO]

ABSTRACT: Topoisomerase IIb (TOP2B) is essential for neural development and function, yet its precise molecular roles remain poorly understood. Here we trapped catalytically engaged TOP2B in DNA cleavage complexes (TOP2Bccs) and mapped their positions genome-wide in cultured mouse cortical neurons. We report that chromosome compartments set the threshold of TOP2B activity within the genome, while specific nucleosome configurations stimulate TOP2B activity within strongly transcribed regions and enhancers. Highly expressed genes that are devoid of usually associated chromatin marks, such as H3K36me3, are deficient in TOP2B activity, indicating that TOP2B may be inefficient at sensing transcription-generated torsional stress directly. Active promoters and the transcription start sites (TSS) with high RNA polymerase II (RNAPII) occupancy show elevated TOP2B ChIP-seq signals but are depleted in TOP2Bccs, indicating that TOP2B is held inactive at active promoters. Surprisingly, TOP2B inhibition with etoposide increased nascent transcription at highly expressed genes and enhancers. While ETP treatment reduced nascent transcription within long genes, these effects were independent of transcript length and instead correlated with the presence of intragenic enhancers. Together these results provide insights into the epigenetic regulation of topoisomerase activity and reveal new roles for TOP2B in neuronal transcriptional regulation.

ORGANISM(S): Mus musculus

PROVIDER: GSE227458 | GEO | 2024/01/29

REPOSITORIES: GEO

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Project description:To compare expression profiles in the cardiomyocytes with wild type top2b and those with top2b deletion after in vivo treatment of mice with doxorubicin or drug vehicle Doxorubicin is widely used in modern cancer treatments, despite the advent of targeted therapy. However, a dose-dependent cardiotoxicity often limits its clinical use. The prevailing theory hypothesizes that doxorubicin-induced cardiotoxicity is the result of reactive oxygen species (ROS) generation due to redox-cycling of doxorubicin. Here we showed that cardiomyocyte-specific deletion of Topoisomerase II beta (Top2b) markedly reduced DNA double-strand breaks, apoptosis, and functional damages in doxorubicin-treated hearts. To investigate transcriptomic changes after doxorubicin treatment in wild type mouse and mouse with cardiac specific deletion of Top2b, we examined the expression profiles in 4 groups of mice (3/group), ie. wildtype mice with or without doxorubicin treatment and mice with Top2b deletion in the cardiomyocytes with or without doxorubicin treatment. Mice were treated with doxorubicin (25mg/kg, i.p.) or PBS (drug vehicle) for 16 hr or 72 hr. The heart was removed and cardiomyocytes were isolated by using a Langendorff apparatus. After purification, total RNA was extracted from the cardiomyocytes, purified, and used for gene expression analysis. Compared with that in control cardiomyocytes or cardiomyocytes with Top2b deletion, doxorubicin caused a significant expression change in the genome of cardiomyocytes from the wildtype mice. Among the changes, multiple genes encoding mitochondrial structural protein and components of the respiratory chain complexes were down-regulated 72 hr after treatment while multiple genes in the p53 pathway were up-regulated 16 hr after treatment in the wildtype cardiomyocytes. Expression changes were examined in 2 groups of mice (wild type and conditional knockout of top2b in the cardiomyocytes) treated with doxorubicin or PBS for 16 or 72 hours

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Mapping catalytically engaged TOP2B in neurons reveals the principles of topoisomerase action within the genome [fastGRO]

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