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Nat Biotechnol. 2019 Aug;37(8):925-936. doi: 10.1038/s41587-019-0206-z. Epub 2019 Aug 2.

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

Author information

1
Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA.
2
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
3
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
4
Biophysics Program, Stanford University School of Medicine, Stanford, CA, USA.
5
Cancer Biology Program, Stanford University School of Medicine, Stanford, CA, USA.
6
Department of Dermatology, Stanford University School of Medicine, Redwood City, CA, USA.
7
10x Genomics, Inc., Pleasanton, CA, USA.
8
10x Genomics, Inc., Pleasanton, CA, USA. grace@10xgenomics.com.
9
Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA. wjg@stanford.edu.
10
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. wjg@stanford.edu.
11
Department of Applied Physics, Stanford University, Stanford, CA, USA. wjg@stanford.edu.
12
Chan Zuckerberg Biohub, San Francisco, CA, USA. wjg@stanford.edu.
13
Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA. howchang@stanford.edu.
14
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. howchang@stanford.edu.
15
Department of Dermatology, Stanford University School of Medicine, Redwood City, CA, USA. howchang@stanford.edu.
16
Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. howchang@stanford.edu.

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.

PMID:
31375813
DOI:
10.1038/s41587-019-0206-z

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