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Nat Med. 2018 May;24(5):580-590. doi: 10.1038/s41591-018-0008-8. Epub 2018 Apr 23.

Transcript-indexed ATAC-seq for precision immune profiling.

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 Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
4
Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.
5
Harvard Society of Fellows, Harvard University, Cambridge, MA, USA.
6
Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA.
7
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
8
Biophysics Program, Stanford University School of Medicine, Stanford, CA, USA.
9
Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
10
Department of Applied Physics, Stanford University, Stanford, CA, USA.
11
Chan Zuckerberg Biohub, San Francisco, CA, USA.
12
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA. mmdavis@stanford.edu.
13
Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. mmdavis@stanford.edu.
14
Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA. mmdavis@stanford.edu.
15
Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA. howchang@stanford.edu.
16
Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA. howchang@stanford.edu.
17
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. howchang@stanford.edu.

Abstract

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.

PMID:
29686426
PMCID:
PMC5948148
DOI:
10.1038/s41591-018-0008-8
[Indexed for MEDLINE]
Free PMC Article

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