Nikolic Ana, Singhal Divya, Ellestad Katrina, Johnston Michael, Shen Yaoqing, Gillmor Aaron, Morrissy Sorana, Cairncross J Gregory, Jones Steven, Lupien Mathieu, Chan Jennifer A, Neri Paola, Bahlis Nizar, Gallo Marco
Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
Sci Adv. 2021 Oct 15;7(42):eabg6045. doi: 10.1126/sciadv.abg6045. Epub 2021 Oct 13.
Single-cell epigenomic assays have tremendous potential to illuminate mechanisms of transcriptional control in functionally diverse cancer cell populations. However, application of these techniques to clinical tumor specimens has been hampered by the current inability to distinguish malignant from nonmalignant cells, which potently confounds data analysis and interpretation. Here, we describe Copy-scAT, an R package that uses single-cell epigenomic data to infer copy number variants (CNVs) that define cancer cells. Copy-scAT enables studies of subclonal chromatin dynamics in complex tumors like glioblastoma. By deploying Copy-scAT, we uncovered potent influences of genetics on chromatin accessibility profiles in individual subclones. Consequently, some genetic subclones were predisposed to acquire stem-like or more differentiated molecular phenotypes, reminiscent of developmental paradigms. Copy-scAT is ideal for studies of the relationships between genetics and epigenetics in malignancies with high levels of intratumoral heterogeneity and to investigate how cancer cells interface with their microenvironment.
单细胞表观基因组分析在阐明功能多样的癌细胞群体中转录调控机制方面具有巨大潜力。然而，由于目前无法区分恶性细胞和非恶性细胞，这些技术在临床肿瘤标本中的应用受到了阻碍，这严重混淆了数据分析和解释。在这里，我们描述了Copy-scAT，一个使用单细胞表观基因组数据来推断定义癌细胞的拷贝数变异（CNV）的R包。Copy-scAT能够研究胶质母细胞瘤等复杂肿瘤中的亚克隆染色质动力学。通过部署Copy-scAT，我们发现了遗传学对单个亚克隆中染色质可及性图谱的强大影响。因此，一些遗传亚克隆倾向于获得干细胞样或更分化的分子表型，这让人联想到发育模式。Copy-scAT非常适合研究肿瘤内异质性高的恶性肿瘤中遗传学与表观遗传学之间的关系，并研究癌细胞如何与其微环境相互作用。
