Transcript-indexed ATAC-seq for precision immune profiling
Open accessAbstract
T cells create vast amounts of diversity in the genes that encode their T cell receptors (TCRs), which enables individual clones to recognize specific peptide-major histocompatibility complex (MHC) ligands. Here we combined sequencing of the TCR-encoding genes with assay for transposase-accessible chromatin with sequencing (ATAC-seq) analysis at the single-cell level to provide information on the TCR specificity and epigenomic state of individual T cells. By using this approach, termed transcript-indexed ATAC-seq (T-ATAC-seq), we identified epigenomic signatures in immortalized leukemic T cells, primary human T cells from healthy volunteers and primary leukemic T cells from patient samples. In peripheral blood CD4+ T cells from healthy individuals, we identified cis and trans regulators of naive and memory T cell states and found substantial heterogeneity in surface-marker-defined T cell populations. In patients with a leukemic form of cutaneous T cell lymphoma, T-ATAC-seq enabled identification of leukemic and nonleukemic regulatory pathways in T cells from the same individual by allowing separation of the signals that arose from the malignant clone from the background T cell noise. Thus, T-ATAC-seq is a new tool that enables analysis of epigenomic landscapes in clonal T cells and should be valuable for studies of T cell malignancy, immunity and immunotherapy.
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ATAC-seq can be performed in single cells, revealing cell-to-cell variability and rare epigenomic phenotypes.
“Importantly, ATAC-seq can be performed in single cells (scATAC-seq), uncovering cell-to-cell variability and rare epigenomic phenotypes (Cusanovich et al., 2018; Satpathy et al., 2018; Buenrostro et al., 2018).”
From Coupled Single-Cell CRISPR Screening and Epigenomic Profiling Reveals Causal Gene Regulatory Networks (2019) · cites this paper as Satpathy et al., 2018
Single-cell ATAC-seq profiles can be paired with orthogonal measurements of RNA or protein expression in the same cell.
“Additionally, scATAC-seq profiles can be paired with orthogonal measurements of RNA or protein expression in the same cell (Satpathy et al., 2018; Chen et al., 2018a).”
From Coupled Single-Cell CRISPR Screening and Epigenomic Profiling Reveals Causal Gene Regulatory Networks (2019) · cites this paper as Satpathy et al., 2018
Prior work has shown that pooling five or more cells accurately reproduces chromatin accessibility profiles.
“previous reports have shown that aggregation of five or more cells is sufficient toaccurately reproduce chromatin accessibility profiles (Satpathy et al., 2018; Schep et al., 2017).”
From Coupled Single-Cell CRISPR Screening and Epigenomic Profiling Reveals Causal Gene Regulatory Networks (2019) · cites this paper as Satpathy et al., 2018
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Self-citation
- Authors
- Satpathy, A. T., Saligrama, N., Buenrostro, J. D., Wei, Y., Wu, B., Rubin, A. J., Granja, J. M., Lareau, C. A., Li, R., Qi, Y., Parker, K. R., Mumbach, M. R., Serratelli, W. S., Gennert, D. G., Schep, A. N., Corces, M. R., Khodadoust, M. S., Kim, Y. H., Khavari, P. A., Greenleaf, W. J., Davis, M. M., & Chang, H. Y.
- Affiliations
- Stanford Medicine (US)
- Broad Institute (US)
- Chan Zuckerberg Biohub San Francisco (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Davis, Mark M.
- Chang, Howard Y.
- ORCID
- Satpathy, Ansuman T.
- Saligrama, Naresha
- Buenrostro, Jason D.
- Rubin, Adam J.
- Granja, Jeffrey M.
- Lareau, Caleb A.
- Li, Rui
- Qi, Yanyan
- Parker, Kevin R.
- Mumbach, Maxwell R.
- Serratelli, William S.
- Gennert, David G.
- Schep, Alicia N.
- Corces, M. Ryan
- Khodadoust, Michael S.
- Kim, Youn H.
- Khavari, Paul A.
- Greenleaf, William J.
- Davis, Mark M.
- Chang, Howard Y.
- Venue
- Nature Medicine
- Published
- 2018-04-23
- Volume
- 24
- Issue
- 5
- Pages
- 580-590
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC5948148
- OpenAlex
- W2801515322
- Cited by
- 152
- References
- 64
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 8 · 2023: 18 · 2022: 15 · 2021: 35 · 2020: 36 · 2019: 21 · 2018: 5
- FWCI
- 8.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (1s10od018220-01)
- National Human Genome Research Institute (P50HG007735, T32HG000044)
- National Institute of General Medical Sciences (T32GM008294)
- National Institute of Allergy and Infectious Diseases (U19AI057229)
- 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 › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- T cell receptor, single-cell epigenomics, T cell receptor diversity, T cell heterogeneity, naive and memory T cells, CD4+ T cells, cutaneous T-cell lymphoma, leukemic T cells, chromatin accessibility, T-cell malignancies, T cell clones, immunotherapy
- MeSH terms
- Cell Line, Transformed, Chromatin, Clone Cells, Humans, Immunity, Leukemia, Receptors, Antigen, T-Cell, RNA, Messenger, CD4-Positive T-Lymphocytes, Jurkat Cells, Transposases, Epigenomics, Single-Cell Analysis, High-Throughput Nucleotide Sequencing
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