Transcript-indexed ATAC-seq for precision immune profiling

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Line, Transformed
  • Chromatin / metabolism*
  • Clone Cells
  • Epigenomics
  • High-Throughput Nucleotide Sequencing / methods*
  • Humans
  • Immunity
  • Jurkat Cells
  • Leukemia / immunology
  • Leukemia / pathology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Antigen, T-Cell / metabolism
  • Single-Cell Analysis
  • Transposases / metabolism*

Substances

  • Chromatin
  • RNA, Messenger
  • Receptors, Antigen, T-Cell
  • Transposases