Tcf1-CTCF cooperativity shapes genomic architecture to promote CD8+ T cell homeostasis

CD8(+) T cell homeostasis is maintained by the cytokines IL-7 and IL-15. Here we show that transcription factors Tcf1 and Lef1 were intrinsically required for homeostatic proliferation of CD8(+) T cells. Multiomics analyses showed that Tcf1 recruited the genome organizer CTCF and that homeostatic cytokines induced Tcf1-dependent CTCF redistribution in the CD8(+) T cell genome. Hi-C coupled with network analyses indicated that Tcf1 and CTCF acted cooperatively to promote chromatin interactions and form highly connected, dynamic interaction hubs in CD8(+) T cells before and after cytokine stimulation. Ablating CTCF phenocopied the proliferative defects caused by Tcf1 and Lef1 deficiency. Tcf1 and CTCF controlled a similar set of genes that regulated cell cycle progression and promoted CD8(+) T cell homeostatic proliferation in vivo. These findings identified CTCF as a Tcf1 cofactor and uncovered an intricate interplay between Tcf1 and CTCF that modulates the genomic architecture of CD8(+) T cells to preserve homeostasis. Xue and colleagues show that Tcf1 and Lef1 recruit the genome organizer CTCF to promote chromatin interactions and form highly connected, dynamic interaction hubs in CD8(+) T cells undergoing homeostatic proliferation.

Automated summary

The study demonstrates that Tcf1 and Lef1 recruit the genome organizer CTCF to promote chromatin interactions and form highly connected, dynamic interaction hubs in CD8(+) T cells undergoing homeostatic proliferation.