TY - JOUR T1 - Massively parallel single-cell chromatin landscapes of human immune cell development and intratumoral T cell exhaustion JF - bioRxiv DO - 10.1101/610550 SP - 610550 AU - Ansuman T. Satpathy AU - Jeffrey M. Granja AU - Kathryn E. Yost AU - Yanyan Qi AU - Francesca Meschi AU - Geoffrey P. McDermott AU - Brett N. Olsen AU - Maxwell R. Mumbach AU - Sarah E. Pierce AU - M. Ryan Corces AU - Preyas Shah AU - Jason C. Bell AU - Darisha Jhutty AU - Corey M. Nemec AU - Jean Wang AU - Li Wang AU - Yifeng Yin AU - Paul G. Giresi AU - Anne Lynn S. Chang AU - Grace X.Y. Zheng AU - William J. Greenleaf AU - Howard Y. Chang Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/04/18/610550.abstract N2 - Understanding complex tissues requires single-cell deconstruction of gene regulation with precision and scale. Here we present a massively parallel droplet-based platform for mapping transposase-accessible chromatin in tens of thousands of single cells per sample (scATAC-seq). We obtain and analyze chromatin profiles of over 200,000 single cells in two primary human systems. In blood, scATAC-seq allows marker-free identification of cell type-specific cis- and trans-regulatory elements, mapping of disease-associated enhancer activity, and reconstruction of trajectories of differentiation from progenitors to diverse and rare immune cell types. In basal cell carcinoma, scATAC-seq reveals regulatory landscapes of malignant, stromal, and immune cell types in the tumor microenvironment. Moreover, scATAC-seq of serial tumor biopsies before and after PD-1 blockade allows identification of chromatin regulators and differentiation trajectories of therapy-responsive intratumoral T cell subsets, revealing a shared regulatory program driving CD8+ T cell exhaustion and CD4+ T follicular helper cell development. We anticipate that droplet-based single-cell chromatin accessibility will provide a broadly applicable means of identifying regulatory factors and elements that underlie cell type and function. ER -