DNA architectural protein CTCF facilitates subset-specific chromatin interactions to limit the formation of memory CD8+ T cells

• DOI: 10.1016/j.immuni.2023.03.017
• Publication Date: 2023-04-10T14:39:58Z
• Authors: Sara Quon; Bingfei Yu; Brendan E. Russ; Kirill Tsyganov; Hongtuyet Nguyen; Clara Toma; Maximilian Heeg; James D. Hocker; J. Justin Milner; Shane Crotty; Matthew E. Pipkin; Stephen J. Turner; Ananda W. Goldrath
• Keywords: CTCF; ChIA-PET

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.