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 Nüssing, Alison Morey, Vibha Udupa, Taylah J. Bennett, Axel Kallies, Cornelis Murre, Phillipe Collas, David Powell, Ananda W. Goldrath, Stephen T. Turner
Abstract
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.