Single-cell epigenomic variability reveals functional cancer heterogeneity.
Single-cell epigenomic variability reveals functional cancer heterogeneity.
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单细胞表观基因组变异性揭示了功能性癌症异质性。
DOI：
10.1186/s13059-016-1133-7
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发表时间：
2017-01-24
期刊：
影响因子：
12.3
通讯作者：
Chang HY
中科院分区：
文献类型：
--
作者：
Litzenburger UM;Buenrostro JD;Wu B;Shen Y;Sheffield NC;Kathiria A;Greenleaf WJ;Chang HY
细胞间的异质性是癌症进化、进展和出现耐药的主要驱动因素。单细胞水平上的表观基因组变异可以迅速造成癌症异质性，但在功能上很难检测和评估。我们开发了一种策略，在单细胞表观基因组学中弥合测量和功能之间的差距。利用K562白血病细胞的单细胞染色质可及性和RNA-SEQ数据，我们发现细胞表面标记CD24与单个细胞中与GATA转录因子相关的染色质可及性变化是协同变化的。荧光激活细胞分选CD24高细胞与低细胞前瞻性分离GATA1和GATA2高细胞与低细胞。GATA高表达细胞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不同敏感性以及不同的自我更新能力。谱系追踪实验表明，GATA/CD24hi细胞有能力在整个起始群体中迅速重建异质性，这表明GATA表达水平驱动了表观基因组可塑性的表型相关来源。单细胞染色质可及性可以指导肿瘤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。本文的在线版本(doi：10.1186/s13059-0161133-7)包含补充材料，授权用户可以使用。
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. The online version of this article (doi:10.1186/s13059-016-1133-7) contains supplementary material, which is available to authorized users.