美国斯坦福大学医学院Howard Y. Chang、William J. Greenleaf和10x基因组学公司Grace X. Y. Zheng团队近日取得一项新成果, 他们开发出大规模平行的单细胞染色质景观的人类免疫细胞发育和瘤内T细胞衰竭。 2019年8月，国际知名学术期刊《自然—生物技术》发表了这一成果。

该课题组研究人员利用测序(sATAC-seq)对大规模并行单细胞内转座酶可进入的染色质作图方法的效能进行了评估。通过scATAC-seq的方法获得了人类血液和基底细胞癌中超过200000个细胞的染色质情况。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，绘制疾病相关的增强子活性和重建细胞分化的轨迹。在基底细胞癌中，ScaAc-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节网络。在程序性细胞死亡蛋白1阻断之前和之后，来自连续肿瘤活组织检查的scATAC-seq谱的分析鉴定了治疗响应性T细胞亚群的染色质调节剂，并揭示了控制肿瘤内CD8T细胞释放和CD4T滤泡辅助细胞发育的共同调节程序。研究人员预计scATAC-seq将能够在不同生物系统中无偏见地发现基因调控因子。

据介绍，理解复杂的组织需要单细胞精确和规模化地解构基因调控。

附：英文原文

Title: Massively parallel single-cell chromatin landscapes of human immune cell development and intratumoral T cell exhaustion

Author: Ansuman T. Satpathy, Jeffrey M. Granja, Kathryn E. Yost, Yanyan Qi, Francesca Meschi, Geoffrey P. McDermott, Brett N. Olsen, Maxwell R. Mumbach, Sarah E. Pierce, M. Ryan Corces, Preyas Shah, Jason C. Bell, Darisha Jhutty, Corey M. Nemec, Jean Wang, Li Wang, Yifeng Yin, Paul G. Giresi, Anne Lynn S. Chang, Grace X. Y. Zheng, William J. Greenleaf, Howard Y. Chang

Issue&Volume: Volume 37 Issue 8

Abstract: 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 type-specific 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.

DOI: 10.1038/s41587-019-0206-z

Source:https://www.nature.com/articles/s41587-019-0206-z