TCF1 dosage determines cell fate during T cell development.

Abstract

Loss-of-function studies have shown that transcription factor T cell factor-1 (TCF1), encoded by the <i>Tcf7</i> gene, is essential for T cell development in the thymus. We discovered that the <i>Tcf7</i> expression level is regulated by E box DNA binding proteins, independent of Notch, and regulates αβ and γδ T cell development. Systematic interrogation of the five E protein binding elements (EPE1-5) in the <i>Tcf7</i> enhancer region showed lineage-specific utilization. Specifically, loss-of-function analysis revealed that only EPE3 plays a critical role in supporting αβ T cell development, while EPE1, 3, and 5 regulate the γδ T cell maturation and functional cell fate decision. The importance of EPE3 in supporting both lineages may stem from its unique capacity to interact with the <i>Tcf7</i> transcriptional start site. Together, these studies demonstrate that the precise dosage of TCF1 expression mediated by distinct EPEs generates a balanced output of T cells from the thymus.