Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2022.11.17.516971v1?rss=1

Authors: Thambyrajah, R., Fadlullah, Z., Proffitt, M., Neo, W. H., Guillen, Y., Casado-Pelaez, M., Herrero-Molinero, P., Brujas, C., Castelluccio, N., Gonzalez, J., Iglesias, A., Marruecos, L., Ruiz-Herguido, C., Esteller, M., Mereu, E., Lacaud, G., Espinosa, L., Bigas, A.

Abstract:
Recent findings are challenging the classical hematopoietic model in which long-term hematopoietic stem cells (LT-HSC) are the base of the hematopoietic system. Clonal dynamics analysis of the hematopoietic system indicate that LT-HSC are not the main contributors of normal hemapoiesis in physiological conditions and the hematopoietic system is mainly maintained by multipotent progenitors (MPPs, hereafter HPC) and LT-HSCs are mostly in a non-active state. The first HSCs emerge from the aorta-gonad and mesonephros (AGM) region along with hematopoietic progenitors (HPC) within hematopoietic clusters. Molecular pathways that determine the HSC fate instead of HPC are still unknown, although inflammatory signaling, including NF-KB has been implicated in the development of HSCs. Here, we identify a chromatin binding function for IKB (also known as the inhibitor of NF-KB) that is Polycomb repression complex 2 (PRC2)- dependent and specifically determines dormant vs proliferating HSCs from the onset of their emergence in the AGM. We find a specific reduction of LT-HSCs in the IKB knockout new-born pups. This defect is manifested at the FL stage already, and traceable to the first emerging HSCs in the E11.5 AGM, without affecting the general HPC population. IKB-deficient LT-HSCs express dormancy signature genes, are less proliferative and can robustly respond to activation stimuli such as in vitro culture and serial transplantation. At the molecular level, we find decreased PRC2-dependent H3K27me3 at the promoters of several retinoic acid signaling elements in the IKB- deficient aortic endothelium and E14.5 FL LT-HSCs. Additionally, IKB binding itself is found in the promoters of retinoic acid receptors rar in the AGM, and rar{gamma} in the LT-HSC of FL. Overall, we demonstrate that the retinoic acid pathway is over-activated in the hematopoietic clusters of IKB-deficient AGMs leading to premature dormancy of LT- HSCs that persists in the FL LT-HSCs.

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