Tcf1 and Lef1 provide constant supervision to mature CD8+ T cell identity and function by organizing genomic architecture

T cell identity is established during thymic development, but how it is maintained in the periphery remains unknown. Here we show that ablating Tcf1 and Lef1 transcription factors in mature CD8(+) T cells aberrantly induces genes from non-T cell lineages. Using high-throughput chromosome-conformation-capture sequencing, we demonstrate that Tcf1/Lef1 are important for maintaining three-dimensional genome organization at multiple scales in CD8(+) T cells. Comprehensive network analyses coupled with genome-wide profiling of chromatin accessibility and Tcf1 occupancy show the direct impact of Tcf1/Lef1 on the T cell genome is to promote formation of extensively interconnected hubs through enforcing chromatin interaction and accessibility. The integrative mechanisms utilized by Tcf1/Lef1 underlie activation of T cell identity genes and repression of non-T lineage genes, conferring fine control of various T cell functionalities. These findings suggest that Tcf1/Lef1 control global genome organization and help form intricate chromatin-interacting hubs to facilitate promoter-enhancer/silencer contact, hence providing constant supervision of CD8(+) T cell identity and function. How CD8(+) T cell identity is maintained after exit from the thymus is not fully established. Here the authors use multiomics approaches including Hi-C to show that Tcf1 and Lef1 prevent aberrant expression of lineage-inappropriate genes by organizing three-dimensional genomic architecture in CD8(+) T cells.

Automated summary

The study demonstrates that Tcf1 and Lef1 play a crucial role in maintaining CD8(+) T cell identity by regulating three-dimensional genome organization and preventing aberrant expression of lineage-inappropriate genes.