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

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.
Competing Interests: Declaration of interests A.W.G. is a member of the scientific advisory board of ArsenalBio. S.J.T. is a member of the scientific advisory board for Medicago, Inc., QC, Canada. No funding from Medicago or ArsenalBio was provided for this work.
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