Abstract: Recent findings suggest that Hematopoietic Stem Cells (HSC) and progenitors arise simultaneously and independently of each other already in the embryonic aorta-gonad mesonephros region, but it is still unknown how their different features are established. Here, we uncover IkBalfa (Nfkbia, the inhibitor of NF-?B) as a critical regulator of HSC proliferation throughout development. IkBalfa balances retinoic acid signaling levels together with the epigenetic silencer, PRC2, specifically in HSCs. Loss of IkBalfa decreases proliferation of HSC and induces a dormancy related gene expression signature instead. Also, IkBalfa deficient HSCs respond with superior activation to in vitro culture and in serial transplantation. At the molecular level, chromatin regions harboring binding motifs for retinoic acid signaling are hypo-methylated for the PRC2 dependent H3K27me3 mark in IkBalfa deficient HSCs. Overall, we show that the proliferation index in the developing HSCs is regulated by a IkBalfa-PRC2 axis, which controls retinoic acid signaling.
