Massively parallel single-cell chromatin landscapes of human immune cell development and intratumoral T cell exhaustion
Massively parallel single-cell chromatin landscapes of human immune cell development and intratumoral T cell exhaustion
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DOI：
10.1038/s41587-019-0206-z
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发表时间：
2019-08-01
影响因子：
46.9
通讯作者：
Chang, Howard Y.
中科院分区：
文献类型：
--
作者：
Satpathy, Ansuman T.;Granja, Jeffrey M.;Chang, Howard Y.
了解复杂的组织需要精确和规模的基因调控的单细胞解构。在这里，我们评估了一种基于大规模并行液滴的方法的性能，该方法用于使用测序（scATAC-seq）在单细胞中映射转座酶可接近的染色质。我们应用scATAC-seq获得了人类血液和基底细胞癌中超过20万个单细胞的染色质谱。在血液中，scATAC-seq的应用使得能够无标记地鉴定细胞类型特异性顺式和反式调节元件，绘制疾病相关增强子活性和重建细胞分化轨迹。在基底细胞癌中，scATAC-seq的应用揭示了肿瘤微环境中恶性细胞、基质细胞和免疫细胞的调控网络。对程序性细胞死亡蛋白1阻断前后的系列肿瘤活检的scATAC-seq图谱进行分析，鉴定了治疗反应性T细胞亚群的染色质调节因子，并揭示了一种共同的调节程序，该程序控制肿瘤内CD 8（+）T细胞耗竭和CD 4（+）T滤泡辅助细胞发育。我们预计scATAC-seq将能够在不同的生物系统中公正地发现基因调控因子。
Understanding complex tissues requires single-cell deconstruction of gene regulation with precision and scale. Here, we assess the performance of a massively parallel droplet-based method for mapping transposase-accessible chromatin in single cells using sequencing (scATAC-seq). We apply scATAC-seq to obtain chromatin profiles of more than 200,000 single cells in human blood and basal cell carcinoma. In blood, application of scATAC-seq enables marker-free identification of cell typespecific cis-and trans-regulatory elements, mapping of disease-associated enhancer activity and reconstruction of trajectories of cellular differentiation. In basal cell carcinoma, application of scATAC-seq reveals regulatory networks in malignant, stromal and immune cells in the tumor microenvironment. Analysis of scATAC-seq profiles from serial tumor biopsies before and after programmed cell death protein 1 blockade identifies chromatin regulators of therapy-responsive T cell subsets and reveals a shared regulatory program that governs intratumoral CD8(+) T cell exhaustion and CD4(+) T follicular helper cell development. We anticipate that scATAC-seq will enable the unbiased discovery of gene regulatory factors across diverse biological systems.