TAL1 is indispensable in ETV2-primed human endothelial cell fate determination.

ETS variant transcription factor 2 (ETV2) serves as a foundational transcription factor for endothelial lineage specification. However, the lineage-specific cofactors that orchestrate with ETV2 during endothelial fate commitment remain elusive. Here, we demonstrate that ETV2 drives the rapid forward programming of human pluripotent stem cells (hPSCs) into endothelial cells (ECs) by direct remodeling of endothelial-specific enhancers. Crucially, we identify T cell acute lymphocytic leukemia protein 1 (TAL1), which is traditionally characterized as a hematopoietic regulator, as an indispensable cofactor for ETV2-mediated endothelial commitment. Distinct from its role in murine development, TAL1 deficiency in hPSCs not only aborts the endothelial program by impairing H3K27ac deposition at key enhancers but also triggers a profound lineage redirection toward a mesenchymal fate. Mechanistically, TAL1 physically interacts with ETV2 to recruit the p300, thereby facilitating a permissive chromatin environment for endothelial identity. By leveraging an hPSC-based differentiation model, our findings establish TAL1 as a master gatekeeper of human EC specification and provide a molecular blueprint for how ETV2-centric complexes synergistically govern human cell fate.