Active maintenance of CD8+ T cell naivety through regulation of global genome architecture
Brendan E. Russ,
Adele Barugahare,
Pushkar Dakle,
Kirril Tsyganov,
Sara Quon,
Bingfei Yu,
Jasmine Li,
Jason K.C. Lee,
Moshe Olshansky,
Zhaohren He,
Paul F. Harrison,
Michael See,
Simone Nussing,
Alison E. Morey,
Vibha A. Udupa,
Taylah J. Bennett,
Axel Kallies,
Cornelis Murre,
Phillipe Collas,
David Powell,
Ananda W. Goldrath,
Stephen J. Turner
Affiliations
Brendan E. Russ
Department of Microbiology, Immunity Theme, Biomedical Discovery Institute, Monash University, Clayton, VIC, Australia; Corresponding author
Adele Barugahare
Department of Microbiology, Immunity Theme, Biomedical Discovery Institute, Monash University, Clayton, VIC, Australia; Bioinformatics Platform, Biomedical Discovery Institute, Monash University, Clayton, VIC, Australia
Pushkar Dakle
Department of Microbiology, Immunity Theme, Biomedical Discovery Institute, Monash University, Clayton, VIC, Australia
Kirril Tsyganov
Department of Microbiology, Immunity Theme, Biomedical Discovery Institute, Monash University, Clayton, VIC, Australia; Bioinformatics Platform, Biomedical Discovery Institute, Monash University, Clayton, VIC, Australia
Sara Quon
Department of Biological Sciences, University of California, San Diego, San Diego, CA, USA
Bingfei Yu
Department of Biological Sciences, University of California, San Diego, San Diego, CA, USA
Jasmine Li
Department of Microbiology, Immunity Theme, Biomedical Discovery Institute, Monash University, Clayton, VIC, Australia; Department of Molecular Biology, University of California, San Diego, San Diego, CA, USA
Jason K.C. Lee
Department of Microbiology, Immunity Theme, Biomedical Discovery Institute, Monash University, Clayton, VIC, Australia
Moshe Olshansky
Department of Microbiology, Immunity Theme, Biomedical Discovery Institute, Monash University, Clayton, VIC, Australia
Zhaohren He
Department of Molecular Biology, University of California, San Diego, San Diego, CA, USA
Paul F. Harrison
Bioinformatics Platform, Biomedical Discovery Institute, Monash University, Clayton, VIC, Australia
Michael See
Bioinformatics Platform, Biomedical Discovery Institute, Monash University, Clayton, VIC, Australia
Simone Nussing
Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
Alison E. Morey
Department of Microbiology, Immunity Theme, Biomedical Discovery Institute, Monash University, Clayton, VIC, Australia
Vibha A. Udupa
Department of Microbiology, Immunity Theme, Biomedical Discovery Institute, Monash University, Clayton, VIC, Australia
Taylah J. Bennett
Department of Microbiology, Immunity Theme, Biomedical Discovery Institute, Monash University, Clayton, VIC, Australia
Axel Kallies
Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia
Cornelis Murre
Department of Molecular Biology, University of California, San Diego, San Diego, CA, USA
Phillipe Collas
Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; Department of Immunology and Transfusion Medicine, Oslo University Hospital, Oslo, Norway
David Powell
Bioinformatics Platform, Biomedical Discovery Institute, Monash University, Clayton, VIC, Australia
Ananda W. Goldrath
Department of Biological Sciences, University of California, San Diego, San Diego, CA, USA
Stephen J. Turner
Department of Microbiology, Immunity Theme, Biomedical Discovery Institute, Monash University, Clayton, VIC, Australia; Corresponding author
Summary: The differentiation of naive CD8+ T lymphocytes into cytotoxic effector and memory CTL results in large-scale changes in transcriptional and phenotypic profiles. Little is known about how large-scale changes in genome organization underpin these transcriptional programs. We use Hi-C to map changes in the spatial organization of long-range genome contacts within naive, effector, and memory virus-specific CD8+ T cells. We observe that the architecture of the naive CD8+ T cell genome is distinct from effector and memory genome configurations, with extensive changes within discrete functional chromatin domains associated with effector/memory differentiation. Deletion of BACH2, or to a lesser extent, reducing SATB1 DNA binding, within naive CD8+ T cells results in a chromatin architecture more reminiscent of effector/memory states. This suggests that key transcription factors within naive CD8+ T cells act to restrain T cell differentiation by actively enforcing a unique naive chromatin state.
