The Hemogenic Competence of Endothelial Progenitors Is Restricted by Runx1 Silencing during Embryonic Development

It is now well-established that hematopoietic stem cells (HSCs) and progenitor cells originate from a specialized subset of endothelium, termed hemogenic endothelium (HE), via an endothelial-to-hematopoietic transition. However, the molecular mechanisms determining which endothelial progenitors possess this hemogenic potential are currently unknown. Here, we investigated the changes in hemogenic potential in endothelial progenitors at the early stages of embryonic development. Using an ETV2::GFP reporter mouse to isolate emerging endothelial progenitors, we observed a dramatic decrease in hemogenic potential between embryonic day (E)7.5 and E8.5. At the molecular level, Runx1 is expressed at much lower levels in E8.5 intra-embryonic progenitors, while Bmi1 expression is increased. Remarkably, the ectopic expression of Runx1 in these progenitors fully restores their hemogenic potential, as does the suppression of BMI1 function. Altogether, our data demonstrate that hemogenic competency in recently specified endothelial progenitors is restrained through the active silencing of Runx1 expression. [Display omitted] •ETV2+ progenitors from E8.5 embryos have very low hemogenic potential•E8.5 ETV2+ progenitors specifically lack Runx1 expression•Ectopic expression of Runx1 confers hemogenic potential to E8.5 ETV2+ progenitors•Runx1 silencing in ETV2+ endothelial progenitors is mediated by BMI1 Hematopoiesis originates from specialized HE at specific stages of embryonic development. Eliades et al. demonstrate that RUNX1 repression is critical for suppressing hemogenic competency in endothelial progenitors at the E8.5 developmental stage and that this is achieved through the silencing of Runx1 transcription by a BMI1-mediated mechanism.