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

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 i...

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Published in:	Cell reports (Cambridge) Vol. 42; no. 10; p. 113301
Main 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.
Format:	Journal Article
Language:	English
Published:	Elsevier Inc 31-10-2023 Cell Press Elsevier
Subjects:	CD8+ T cell chromatin CP: Immunology CP: Molecular biology T cell memory CP: Immunology CP: Molecular biology chromatin CD8+ T cell T cell memory
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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. [Display omitted] •CD8+ T cell differentiation states are underscored by distinct chromatin looping architectures•Chromatin loops connect CD8+ T cell subset-specific enhancers, transcription factors and genes•Effector and memory CTLs have similar genome architectures, explaining rapid memory recall•BACH2, and to a lesser extent, SATB1, enforce a naive CD8+ T cell loop architecture Russ et al. use Hi-C to map chromatin architecture dynamics during virus-specific CD8+ T cell differentiation. They demonstrate that key transcription factors preserve naivety by enforcing a naive chromatin state, and that effector and memory states are largely similar, providing a molecular explanation for rapid memory T cell function.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS Conceptualization, B.E.R., S.Q., B.Y., and S.J.T.; methodology, B.E.R., J.L., K.T., and P.D.; investigation, B.E.R., B.Y., J.L., J.K.C., S.N., A.E.M., V.A.U., T.J.B., I.A.P., and A.L.S.; software, K.T.; formal analysis, B.E.R., K.T., P.D., M.O., Z.H., P.F.H., A.B., M.S., and D.P.; resources, A.K.; writing - original draft, B.E.R.; writing - reviewing & editing, B.E.R., S.J.T., S.Q., A.W.G., P.C., C.M., and A.K.; supervision, S.J.T., A.W.G., D.P., C.M., and P.C.; funding acquisition, S.J.T. A.W.G., and C.M.
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2023.113301