Active maintenance of CD8+ T cell naivety through regulation of global genome architecture

Authors:

• Russ, Brendan E.
• Barugahare, Adele
• Dakle, Pushkar
• Tsyganov, Kirril
• Quon, Sara
• Yu, Bingfei
• Li, Jasmine
• Lee, Jason K.C.
• Olshansky, Moshe
• He, Zhaohren
• Harrison, Paul F.
• See, Michael
• Nussing, Simone
• Morey, Alison E.
• Udupa, Vibha A.
• Bennett, Taylah J.
• Kallies, Axel
• Murre, Cornelis
• Collas, Phillipe
• Powell, David
• Goldrath, Ananda W.
• Turner, Stephen J.

Details:

Cell Reports, Volume 42, Issue 10, 2023-10-31

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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.