TY - JOUR
T1 - Transcript-indexed ATAC-seq for precision immune profiling
AU - Satpathy, Ansuman T.
AU - Saligrama, Naresha
AU - Buenrostro, Jason D.
AU - Wei, Yuning
AU - Wu, Beijing
AU - Rubin, Adam J.
AU - Granja, Jeffrey M.
AU - Lareau, Caleb A.
AU - Li, Rui
AU - Qi, Yanyan
AU - Parker, Kevin R.
AU - Mumbach, Maxwell R.
AU - Serratelli, William S.
AU - Gennert, David G.
AU - Schep, Alicia N.
AU - Corces, M. Ryan
AU - Khodadoust, Michael S.
AU - Kim, Youn H.
AU - Khavari, Paul A.
AU - Greenleaf, William J.
AU - Davis, Mark M.
AU - Chang, Howard Y.
N1 - Funding Information:
We thank members of the Chang, Davis and Greenleaf laboratories, including Y. Shen and K. Qu, for helpful discussions. We thank X. Ji, D. Wagh and J. Coller at the Stanford Functional Genomics Facility. This work was supported by the Parker Institute for Cancer Immunotherapy (A.T.S., H.Y.C. and M.M.D.), the US National Institutes of Health (NIH) grants P50HG007735 (H.Y.C. and W.J.G.), 5U19AI057229 (M.M.D.), and U19AI057266 (W.J.G), and the Scleroderma Research Foundation (H.Y.C.). A.T.S. was supported by a Parker Bridge Scholar Award from the Parker Institute for Cancer Immunotherapy and a Cancer Research Institute Irvington Fellowship from the Cancer Research Institute. N.S. was supported by the National Multiple Sclerosis Society Postdoctoral Fellowship. J.D.B. acknowledges the Broad Institute Fellows and Harvard Society of Fellows programs for funding. M.R.C. was supported by a grant from the Leukemia and Lymphoma Society Career Development Program. W.J.G. is a Chan Zuckerberg Biohub investigator. M.M.D. is an investigator of the Howard Hughes Medical Institute. Sequencing was performed by the Stanford Functional Genomics Facility (which is supported by NIH grant S10OD018220).
Funding Information:
We thank members of the Chang, Davis and Greenleaf laboratories, including Y. Shen and K. Qu, for helpful discussions. We thank X. Ji, D. Wagh and J. Coller at the Stanford Functional Genomics Facility. This work was supported by the Parker Institute for Cancer Immunotherapy (A.T.S., H.Y.C. and M.M.D.), the US National Institutes of Health (NIH) grants P50HG007735 (H.Y.C. and W.J.G.), 5U19AI057229 (M.M.D.), and U19AI057266 (W.J.G), and the Scleroderma Research Foundation (H.Y.C.). A.T.S. was supported by a Parker Bridge Scholar Award from the Parker Institute for Cancer Immunotherapy and a Cancer Research Institute Irvington Fellowship from the Cancer Research Institute. N.S. was supported by the National Multiple Sclerosis Society Postdoctoral Fellowship. J.D.B. acknowledges the Broad Institute Fellows and Harvard Society of Fellows programs for funding. M.R.C. was supported by a grant from the Leukemia and Lymphoma Society Career Development Program. W.J.G. is a Chan Zuckerberg Biohub investigator. M.M.D. is an investigator of the Howard Hughes Medical Institute. Sequencing was performed by the Stanford Functional Genomics Facility (which is supported by cc grant S10OD018220).
Publisher Copyright:
© 2018 Nature America Inc., part of Springer Nature. All rights reserved.
PY - 2018/5/1
Y1 - 2018/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85045857015&partnerID=8YFLogxK
U2 - 10.1038/s41591-018-0008-8
DO - 10.1038/s41591-018-0008-8
M3 - Article
C2 - 29686426
AN - SCOPUS:85045857015
SN - 1078-8956
VL - 24
SP - 580
EP - 590
JO - Nature medicine
JF - Nature medicine
IS - 5
ER -