ZEB1 drives terminal erythroid maturation by controlling the GATA2-KLF1 regulatory switch.

Erythropoiesis is a highly coordinated process governed by lineage-defining transcription factors. While several master regulators have been characterized, many additional factors expressed in erythroid progenitors remain poorly understood. Here, we identify the epithelial-to-mesenchymal transition (EMT)-associated transcription factor ZEB1 as a previously unrecognized regulator of erythroid maturation. ZEB1 is expressed in murine and human erythroid progenitors, and its loss impairs proliferation and disrupts the erythroid transcriptional network. Mechanistically, ZEB1 interacts with KLF1 and governs both its expression dynamics and nuclear localization. In ZEB1-deficient cells, GATA2 silencing is delayed due to failure of KLF1 to properly accumulate in the nucleus, impairing KLF1-mediated repression of GATA2 and perturbing the GATA2-KLF1 regulatory switch that drives late-stage erythropoiesis. Consistent with these findings, ZEB1 downregulation hampers maturation of primary human CD34⁺-derived erythroid cells. Together, our findings establish KLF1 as a repressor of GATA2, and ZEB1 as a critical enforcer of erythroid transcriptional circuitry, and demonstrate that erythroid cells recruit EMT-associated factors to ensure lineage completion.