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在神经元中绘制催化活性的 TOP2B,揭示了拓扑异构酶在基因组内作用的原理。

Mapping catalytically engaged TOP2B in neurons reveals the principles of topoisomerase action within the genome.

机构信息

Departments of Psychiatry, Neuroscience, and Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Peter O' Donnell Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Departments of Psychiatry, Neuroscience, and Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Peter O' Donnell Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.

出版信息

Cell Rep. 2024 Feb 27;43(2):113809. doi: 10.1016/j.celrep.2024.113809. Epub 2024 Feb 19.

Abstract

We trapped catalytically engaged topoisomerase IIβ (TOP2B) in covalent DNA cleavage complexes (TOP2Bccs) and mapped their positions genome-wide in cultured mouse cortical neurons. We report that TOP2Bcc distribution varies with both nucleosome and compartmental chromosome organization. While TOP2Bccs in gene bodies correlate with their level of transcription, highly expressed genes that lack the usually associated chromatin marks, such as H3K36me3, show reduced TOP2Bccs, suggesting that histone posttranslational modifications regulate TOP2B activity. Promoters with high RNA polymerase II occupancy show elevated TOP2B chromatin immunoprecipitation sequencing signals but low TOP2Bccs, indicating that TOP2B catalytic engagement is curtailed at active promoters. Surprisingly, either poisoning or inhibiting TOP2B increases nascent transcription at most genes and enhancers but reduces transcription within long genes. These effects are independent of transcript length and instead correlate with the presence of intragenic enhancers. Together, these results clarify how cells modulate the catalytic engagement of topoisomerases to affect transcription.

摘要

我们将催化活性的拓扑异构酶 IIβ(TOP2B)捕获在共价 DNA 断裂复合物(TOP2Bccs)中,并在培养的小鼠皮质神经元中对其在全基因组范围内的位置进行了作图。我们报告说,TOP2Bcc 的分布与核小体和区室染色体组织都有关。虽然基因体内的 TOP2Bccs 与其转录水平相关,但缺乏通常相关的染色质标记(如 H3K36me3)的高度表达基因显示出减少的 TOP2Bccs,这表明组蛋白翻译后修饰调节 TOP2B 活性。具有高 RNA 聚合酶 II 占有率的启动子显示出升高的 TOP2B 染色质免疫沉淀测序信号,但 TOP2Bccs 较低,表明 TOP2B 的催化结合在活跃的启动子处受到抑制。令人惊讶的是,TOP2B 的毒害或抑制作用会增加大多数基因和增强子的新生转录,但会减少长基因内的转录。这些效应不依赖于转录本长度,而是与基因内增强子的存在相关。总之,这些结果阐明了细胞如何调节拓扑异构酶的催化结合以影响转录。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7969/11064056/7311b95b0a82/nihms-1970904-f0001.jpg

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