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 re-vealed that weak-affinity CTCF binding promotes terminal differentiation of CD8+ T cells through the regula-tion 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.

Automated summary

Using the Hi-C technique, we investigated the relationship between genome configuration and CD8+ T cell differentiation. We found that CTCF mutations can affect the expression of terminal-effector genes, indicating that CTCF not only participates in genome organization, but also regulates the diversity of effector CD8+ T cells by altering interactions that regulate the transcription factor landscape and transcriptome.