Litzenburger Ulrike M, Buenrostro Jason D, Wu Beijing, Shen Ying, Sheffield Nathan C, Kathiria Arwa, Greenleaf William J, Chang Howard Y
Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Genome Biol. 2017 Jan 24;18(1):15. doi: 10.1186/s13059-016-1133-7.
Cell-to-cell heterogeneity is a major driver of cancer evolution, progression, and emergence of drug resistance. Epigenomic variation at the single-cell level can rapidly create cancer heterogeneity but is difficult to detect and assess functionally.
We develop a strategy to bridge the gap between measurement and function in single-cell epigenomics. Using single-cell chromatin accessibility and RNA-seq data in K562 leukemic cells, we identify the cell surface marker CD24 as co-varying with chromatin accessibility changes linked to GATA transcription factors in single cells. Fluorescence-activated cell sorting of CD24 high versus low cells prospectively isolated GATA1 and GATA2 high versus low cells. GATA high versus low cells express differential gene regulatory networks, differential sensitivity to the drug imatinib mesylate, and differential self-renewal capacity. Lineage tracing experiments show that GATA/CD24hi cells have the capability to rapidly reconstitute the heterogeneity within the entire starting population, suggesting that GATA expression levels drive a phenotypically relevant source of epigenomic plasticity.
Single-cell chromatin accessibility can guide prospective characterization of cancer heterogeneity. Epigenomic subpopulations in cancer impact drug sensitivity and the clonal dynamics of cancer evolution.
细胞间异质性是癌症进化、进展及耐药性产生的主要驱动因素。单细胞水平的表观基因组变异可迅速产生癌症异质性，但难以在功能上进行检测和评估。
我们开发了一种策略，以弥合单细胞表观基因组学中测量与功能之间的差距。利用K562白血病细胞中的单细胞染色质可及性和RNA测序数据，我们确定细胞表面标志物CD24与单细胞中与GATA转录因子相关的染色质可及性变化共同变化。对CD24高表达与低表达细胞进行荧光激活细胞分选，可前瞻性地分离出GATA1和GATA2高表达与低表达细胞。GATA高表达与低表达细胞表达不同的基因调控网络，对甲磺酸伊马替尼的敏感性不同，自我更新能力也不同。谱系追踪实验表明，GATA/CD24hi细胞有能力迅速重建整个起始群体中的异质性，这表明GATA表达水平驱动了表观基因组可塑性的一个表型相关来源。
单细胞染色质可及性可指导癌症异质性的前瞻性表征。癌症中的表观基因组亚群影响药物敏感性和癌症进化的克隆动力学。
