1. DNA architectural protein CTCF facilitates subset-specific chromatin interactions to limit the formation of memory CD8+ T cells.
- Author
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Quon, Sara, Yu, Bingfei, Russ, Brendan, Tsyganov, Kirill, Nguyen, Hongtuyet, Toma, Clara, Heeg, Maximilian, Hocker, James, Milner, J, Crotty, Shane, Pipkin, Matthew, Turner, Stephen, and Goldrath, Ananda
- Subjects
CD8(+) T cell ,CTCF ,Hi-C ,enhancer ,epigenetics ,genome organization ,promoter ,Humans ,Binding Sites ,CCCTC-Binding Factor ,CD8-Positive T-Lymphocytes ,Chromatin ,DNA ,Protein Binding ,Repressor Proteins - Abstract
Although the importance of genome organization for transcriptional regulation of cell-fate decisions and function is clear, the changes in chromatin architecture and how these impact effector and memory CD8+ T cell differentiation remain unknown. Using Hi-C, we studied how genome configuration is integrated with CD8+ T cell differentiation during infection and investigated the role of CTCF, a key chromatin remodeler, in modulating CD8+ T cell fates through CTCF knockdown approaches and perturbation of specific CTCF-binding sites. We observed subset-specific changes in chromatin organization and CTCF binding and revealed that weak-affinity CTCF binding promotes terminal differentiation of CD8+ T cells through the regulation of transcriptional programs. Further, patients with de novo CTCF mutations had reduced expression of the terminal-effector genes in peripheral blood lymphocytes. Therefore, in addition to establishing genome architecture, CTCF regulates effector CD8+ T cell heterogeneity through altering interactions that regulate the transcription factor landscape and transcriptome.
- Published
- 2023