Cited by 999Single-cell and spatial transcriptomicsGenomics and Chromatin DynamicsChromatin Remodeling and Cancer

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

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Satpathy, Ansuman T., Granja, Jeffrey M., Yost, Kathryn E., Qi, Yanyan, Meschi, Francesca, McDermott, Geoffrey P., Olsen, Brett N., Mumbach, Maxwell R., Pierce, Sarah E., Corces, M. Ryan, Shah, Preyas, Bell, Jason C., Jhutty, Darisha, Nemec, Corey M., Wang, Jean, Wang, Li, Yin, Yifeng, Giresi, Paul G., Chang, Anne Lynn S., Zheng, Grace X. Y., Greenleaf, William J., Chang, Howard Y.·2019·Nature Biotechnology

DOI 10.1038/s41587-019-0206-zPMC PMC7299161

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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.

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Authors: Satpathy, A. T., Granja, J. M., Yost, K. E., Qi, Y., Meschi, F., McDermott, G. P., Olsen, B. N., Mumbach, M. R., Pierce, S. E., Corces, M. R., Shah, P., Bell, J. C., Jhutty, D., Nemec, C. M., Wang, J., Wang, L., Yin, Y., Giresi, P. G., Chang, A. L. S., Zheng, G. X. Y., Greenleaf, W. J., & Chang, H. Y.
Affiliations: Stanford Medicine (US)
10X Genomics (United States) (US)
Chan Zuckerberg Biohub San Francisco (US)
Howard Hughes Medical Institute (US)
Corresponding author: Zheng, Grace X. Y.
Greenleaf, William J.
Chang, Howard Y.
ORCID: Satpathy, Ansuman T.
Granja, Jeffrey M.
Yost, Kathryn E.
Qi, Yanyan
Mumbach, Maxwell R.
Pierce, Sarah E.
Corces, M. Ryan
Bell, Jason C.
Nemec, Corey M.
Yin, Yifeng
Chang, Anne Lynn S.
Zheng, Grace X. Y.
Greenleaf, William J.
Chang, Howard Y.
Venue: Nature Biotechnology
Publisher: Springer Science and Business Media LLC
Published: 2019-08
Volume: 37
Issue: 8
Pages: 925-936
ISSN: 0733-222X (ISSN-L)
1087-0156
1546-1696
DOI: 10.1038/s41587-019-0206-z
PMC: PMC7299161
OpenAlex: W2965985232
Cited by: 980
References: 86
Citations by year: 2026: 121 · 2025: 170 · 2024: 145 · 2023: 162 · 2022: 137 · 2021: 157 · 2020: 75 · 2019: 12
FWCI: 33.66
Type: journal article
Language: en
Open access: green
doi.org
Licence: cc-by
www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Biotechnology (publishedVersion)
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (K08CA23188-01, P50HG007735)
Parker Foundation
Howard Hughes Medical Institute
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords: single-cell ATAC-seq, immune cell development, basal cell carcinoma, tumor microenvironment, T cell exhaustion, CD8+ T cells, enhancer activity, anti-PD-1 therapy, gene regulatory networks, next-generation sequencing
MeSH terms: Bone Marrow Cells, Cell Line, Chromatin, Computer Simulation, Gene Expression Regulation, Hematopoiesis, Humans, Leukocytes, Mononuclear, T-Lymphocytes, Transcription Factors, Single-Cell Analysis, High-Throughput Nucleotide Sequencing

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

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