CBFβ initiates the hematopoietic stem cell program without obligatory binding to RUNX

Abstract

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, CBF{beta}, and that a CBF{beta}-binding-deficient Runx1 mutant form can activate the HE program in the DA. Nevertheless, CBF{beta} 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 CBF{beta} binding to Runx is not detrimental for DH, confirming that CBF{beta} functions independently of Runx. Thus, we have uncovered, for the first time, that CBF{beta} regulates gene expression without Runx, breaking the dogma in which CBF{beta} s gene regulatory functions are strictly dependent on its binding to Runx.\n\nHIGHLIGHTSO_LIRunx1 and CBF{beta} play independent roles in the establishment of the HSC lineage\nC_LIO_LIRunx1 binding to CBF{beta} is not required for HE establishment\nC_LIO_LICBF{beta} is downstream of BMP and regulates endogenous VEGFA expression in DH\nC_LIO_LIBinding to Runx is not obligatory for CBF{beta} function\nC_LI