Nat Commun

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 I kappa B alpha (Nfkbia, the inhibitor of NF-kappa B) as a critical regulator of HSC proliferation throughout development. I kappa B alpha balances retinoic acid signaling levels together with the epigenetic silencer, PRC2, specifically in HSCs. Loss of I kappa B alpha decreases proliferation of HSC and induces a dormancy related gene expression signature instead. Also, I kappa B alpha 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 I kappa B alpha deficient HSCs. Overall, we show that the proliferation index in the developing HSCs is regulated by a I kappa B alpha-PRC2 axis, which controls retinoic acid signaling. Hematopoietic stem cells are generated during development, though how and when they become dormant long term-HSCs remains unclear. Here they show that retinoic acid receptor levels are regulated by a I kappa B alpha-PRC2 axis in HSCs, and that I kappa B alpha KO mice have HSCs that are fewer in number, but functionally and molecularly more dormant.