Lineage-Determining Transcription Factor TCF-1 Initiates the Epigenetic Identity of T Cells

T cell development is orchestrated by transcription factors that regulate the expression of genes initially buried within inaccessible chromatin, but the transcription factors that establish the regulatory landscape of the T cell lineage remain unknown. Profiling chromatin accessibility at eight stages of T cell development revealed the selective enrichment of TCF-1 at genomic regions that became accessible at the earliest stages of development. TCF-1 was further required for the accessibility of these regulatory elements and at the single-cell level, it dictated a coordinate opening of chromatin in T cells. TCF-1 expression in fibroblasts generated de novo chromatin accessibility even at chromatin regions with repressive marks, inducing the expression of T cell-restricted genes. These results indicate that a mechanism by which TCF-1 controls T cell fate is through its widespread ability to target silent chromatin and establish the epigenetic identity of T cells. [Display omitted] •TCF-1 drives the early wave of chromatin accessibility in T cell development•Tcf7−/− mice cannot establish the open chromatin landscape of normal T cells•At the single-cell level, TCF-1 dictates a coordinate opening of the chromatin•TCF-1 can erase repressive marks and activate T cell-restricted genes in fibroblasts It is known that TCF-1 is required for T cell development, but the mechanism by which it controls the T cell lineage remains unclear. Johnson et al. reveal that TCF-1 controls T cell fate through its ability to create de novo open chromatin, establishing the epigenetic identity of T cells.