IκBα controls dormancy in hematopoietic stem cells via retinoic acid during embryonic development

Thambyrajah R, Maqueda M, Fadlullah MZ, Proffitt M, Neo WH, Guillén Y, Casado-Pelaez M, Herrero-Molinero P, Brujas C, Castelluccio N, González J, Iglesias A, Marruecos L, Ruiz-Herguido C, Esteller M, Mereu E, Lacaud G, Espinosa L, Bigas A.

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.

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