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, and Chang, Howard Y
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.