文章：

RNA聚合酶II在组蛋白基因中的作用可预测人类癌症的预后

RNA polymerase II at histone genes predicts outcome in human cancer

原文发布日期：2025-02-13

DOI: 10.1126/science.ads2169

类型: Research Article

开放获取: 否

文章简介：

Editor’s summary

Cancer often exhibits genome-wide hypertranscription, but the mechanisms driving this phenomenon remain unclear. To understand how increased transcription might contribute to cancer progression, Henikoff et al. investigated RNA polymerase II (RNAPII) activity across different tumor types. Mapping RNAPII activity across the whole genome in tumor and normal tissues, the authors found widespread transcriptional changes. They also discovered that RNAPII occupancy at histone genes correlated with tumor aggressiveness, particularly in meningiomas and breast cancers. Elevated RNAPII at histone genes predicted rapid cancer recurrence and corresponded to chromosome losses, suggesting that histone gene hypertranscription may drive overproliferation and genomic instability in cancer. —Di Jiang

Abstract

Genome-wide hypertranscription is common in human cancer and predicts poor prognosis. To understand how hypertranscription might drive cancer, we applied our formalin-fixed paraffin-embedded (FFPE)–cleavage under targeted accessible chromatin method for mapping RNA polymerase II (RNAPII) genome-wide in FFPE sections. We demonstrate global RNAPII elevations in mouse gliomas and assorted human tumors in small clinical samples and discover regional elevations corresponding to de novo HER2 amplifications punctuated by likely selective sweeps. RNAPII occupancy at S-phase-dependent histone genes correlated with WHO grade in meningiomas, accurately predicted rapid recurrence, and corresponded to whole-arm chromosome losses. Elevated RNAPII at histone genes in meningiomas and diverse breast cancers is consistent with histone production being rate-limiting for S-phase progression and histone gene hypertranscription driving overproliferation and aneuploidy in cancer, with general implications for precision oncology.

简介翻译： 

编者概要

癌症常表现出全基因组的超转录，但驱动这一现象的机制仍不明确。为理解转录增加如何促进癌症进展，Henikoff等人研究了不同肿瘤类型中RNA聚合酶II（RNAPII）的活性。通过绘制肿瘤和正常组织中全基因组的RNAPII活性，作者发现了广泛的转录变化。他们还发现，组蛋白基因处的RNAPII占用与肿瘤侵袭性相关，尤其在脑膜瘤和乳腺癌中。组蛋白基因处升高的RNAPII预示着癌症快速复发，并与染色体缺失相对应，这表明组蛋白基因的超转录可能驱动癌症中的过度增殖和基因组不稳定性。——Di Jiang

摘要

全基因组超转录在人类癌症中常见，并预示着不良预后。为理解超转录如何驱动癌症，我们应用了针对福尔马林固定石蜡包埋（FFPE）样本中可及染色质靶向切割的方法，以绘制FFPE切片中全基因组的RNA聚合酶II（RNAPII）。我们在小鼠胶质瘤和各种人类肿瘤的小型临床样本中证明了全局RNAPII的升高，并发现了与从头HER2扩增相对应的区域升高，其间可能穿插着选择性清除。在脑膜瘤中，S期依赖性组蛋白基因处的RNAPII占用与WHO分级相关，能准确预测快速复发，并与全臂染色体缺失相对应。脑膜瘤和多种乳腺癌中组蛋白基因处升高的RNAPII，与组蛋白生产成为S期进程的限速因素以及组蛋白基因超转录驱动癌症中的过度增殖和非整倍体相一致，这对精准肿瘤学具有普遍意义。

原文链接：

RNA polymerase II at histone genes predicts outcome in human cancer