axis regulates lineage commitment during endothelial-to-hematopoietic transition from human pluripotent stem cells.

PU.1 () is pivotal in hematopoiesis, yet its role in human endothelial-to-hematopoietic transition (EHT) remains unclear. Comparing human and EHT transcriptomes revealed 's regulatory role. Knocking down during EHT led to a decrease in the generation of hematopoietic progenitor cells (HPCs) and their differentiation potential. Through multi-omic analysis, we identified and - transcription factors specific to erythroid/myeloid and lymphoid cells, respectively - as downstream targets of . Overexpressing or partially rescues the knockdown-induced reduction in HPC formation. Specifically, overexpression restores myeloid lineage potential, while overexpression re-establishes lymphoid lineage potential. We also observed a - axis in the regulatory network in EHT. Taken together, our findings shed new light on the role of in regulating lineage commitment during EHT, potentially contributing to the heterogeneity of hematopoietic stem cells (HSCs).