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Open Access Publications from the University of California

Transcript-indexed ATAC-seq for precision immune profiling.

  • Author(s): Satpathy, Ansuman T
  • Saligrama, Naresha
  • Buenrostro, Jason D
  • Wei, Yuning
  • Wu, Beijing
  • 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
  • et al.

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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