Massively parallel single-cell chromatin landscapes of human immune cell development and intratumoral T cell exhaustion
Ansuman T. Satpathy,
Jeffrey M. Granja,
Kathryn E. Yost,
Geoffrey P McDermott,
Brett N Olsen,
Maxwell R. Mumbach,
Sarah E Pierce,
M. Ryan Corces,
Jason C. Bell,
Corey M Nemec,
Paul G Giresi,
Anne Lynn S. Chang,
Grace X.Y. Zheng,
William J. Greenleaf,
Howard Y. Chang
Posted 18 Apr 2019
bioRxiv DOI: 10.1101/610550 (published DOI: 10.1038/s41587-019-0206-z)
Posted 18 Apr 2019
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.
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