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SUMMARY Hematopoietic stem cells (HSCs) emerge from hemogenic endothelium (HE) localised in the embryonic dorsal aorta (DA). Here we show that Runx1, a transcription factor essential for HSC emergence, controls HE establishment in the absence of its non-DNA-binding partner, CBFβ, and that a CBFβ-binding-deficient Runx1 mutant form can activate the HE program in the DA. Nevertheless, CBFβ is also essential for HSC emergence by regulating the specification of definitive hemangioblasts (DHs), the precursors of the DA and HE, in the lateral plate mesoderm where it mediates VEGFA induction by BMP signalling. Surprisingly, no Runx gene is expressed in DHs and the pharmacological inhibition of CBFβ binding to Runx is not detrimental for DH, confirming that CBFβ functions independently of Runx. Thus, we have uncovered, for the first time, that CBFβ regulates gene expression without Runx, breaking the dogma in which CBFβ ‘s gene regulatory functions are strictly dependent on its binding to Runx. HIGHLIGHTS <jats:list list-type="bullet"><jats:list-item> Runx1 and CBFβ play independent roles in the establishment of the HSC lineage <jats:list-item> Runx1 binding to CBFβ is not required for HE establishment <jats:list-item> CBFβ is downstream of BMP and regulates endogenous VEGFA expression in DH <jats:list-item> Binding to Runx is not obligatory for CBFβ function

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