Interrogating regulatory epigenetic alterations during tumor progression at the resolution of single cells has remained an understudied area of research. Here we developed a highly sensitive single-nucleus CUT&RUN (snCUT&RUN) assay to profile histone modifications in isogenic primary, metastatic, and cisplatin-resistant head and neck squamous cell carcinoma (HNSCC) patient-derived tumor cell lines. We find that the epigenome can be involved in diverse modes to contribute towards HNSCC progression. First, we demonstrate that gene expression changes during HNSCC progression can be comodulated by alterations in both copy number and chromatin activity, driving epigenetic rewiring of cell states. Furthermore, intratumour epigenetic heterogeneity (ITeH) may predispose subclonal populations within the primary tumour to adapt to selective pressures and foster the acquisition of malignant characteristics. In conclusion, snCUT&RUN serves as a valuable addition to the existing toolkit of single-cell epigenomic assays and can be used to dissect the functionality of the epigenome during cancer progression.

中文翻译：

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单核 CUT&RUN 阐明了内在和基因组学驱动的表观遗传异质性在头颈癌进展中的功能


在单细胞分辨率下询问肿瘤进展过程中的调节性表观遗传改变仍然是一个研究不足的研究领域。在这里，我们开发了一种高灵敏度的单核 CUT&RUN （snCUT&RUN） 测定法，用于分析同基因原发性、转移性和顺铂耐药性头颈部鳞状细胞癌 （HNSCC） 患者来源的肿瘤细胞系中的组蛋白修饰。我们发现表观基因组可以参与多种模式，以促进 HNSCC 进展。首先，我们证明 HNSCC 进展过程中的基因表达变化可以通过拷贝数和染色质活性的改变进行共调节，从而驱动细胞状态的表观遗传重新布线。此外，肿瘤内表观遗传异质性 （ITeH） 可能使原发肿瘤内的亚克隆群体易感性，以适应选择压力并促进恶性特征的获得。总之，snCUT&RUN 是现有单细胞表观基因组检测工具包的宝贵补充，可用于剖析癌症进展过程中表观基因组的功能。