Lineage relationship of CD8(+) T cell subsets is revealed by progressive changes in the epigenetic landscape.
To better elucidate epigenetic mechanisms that correlate with the dynamic gene expression program observed upon T-cell differentiation, we investigated the genomic landscape of histone modifications in naive and memory CD8(+) T cells. Using a ChIP-Seq approach coupled with global gene expression profiling, we generated genome-wide histone H3 lysine 4 (H3K4me3) and H3 lysine 27 (H3K27me3) trimethylation maps in naive, T memory stem cells, central memory cells, and effector memory cells in order to gain insight into how histone architecture is remodeled during T cell differentiation. We show that H3K4me3 histone modifications are associated with activation of genes, while H3K27me3 is negatively correlated with gene expression at canonical loci and enhancers associated with T-cell metabolism, effector function, and memory. Our results also reveal histone modifications and gene expression signatures that distinguish the recently identified T memory stem cells from other CD8(+) T-cell subsets. Taken together, our results suggest that CD8(+) lymphocytes undergo chromatin remodeling in a progressive fashion. These findings have major implications for our understanding of peripheral T-cell ontogeny and the formation of immunological memory.
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.|Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
Joseph G
JG
Crompton
Systems Genomics and Bioinformatics Unit, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Manikandan
M
Narayanan
Department of Environmental Medicine, New York University School of Medicine,Tuxedo, NY 10987, USA.
Suresh
S
Cuddapah
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Rahul
R
Roychoudhuri
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Yun
Y
Ji
Department of Physics, The George Washington University, Washington, DC 20052, USA.
Wenjing
W
Yang
Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007, United States, Bethesda, MD 20892, USA.
Shashank J
SJ
Patel
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Madhusudhanan
M
Sukumar
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Douglas C
DC
Palmer
Department of Physics, The George Washington University, Washington, DC 20052, USA.
Weiqun
W
Peng
Research Branch, Sidra Medical and Research Centre, Doha, Qatar.|Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
Ena
E
Wang
Research Branch, Sidra Medical and Research Centre, Doha, Qatar.|Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
Francesco M
FM
Marincola
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.|Clinical Investigator Development Program, NCI/NIH, Bethesda, MD 20892, USA.
Christopher A
CA
Klebanoff
Systems Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Keji
K
Zhao
Systems Genomics and Bioinformatics Unit, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
John S
JS
Tsang
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Luca
L
Gattinoni
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Nicholas P
NP
Restifo
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D019070:Cell Lineage / Q000235:genetics* / Q000276:immunology*; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D006657:Histones / Q000378:metabolism; D007156:Immunologic Memory / Q000235:genetics; D016131:Lymphocyte Subsets / Q000378:metabolism; D008745:Methylation; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic / Q000235:genetics; D011499:Protein Processing, Post-Translational
D006657:Histones