TY - JOUR
T1 - IκBα controls dormancy in hematopoietic stem cells via retinoic acid during embryonic development.
AU - Thambyrajah, Roshana
AU - Maqueda, M
AU - Wilmot, Muhammad Zaki H Fadlullah
AU - Proffitt, M
AU - Neo, Wen Hao
AU - Guillén, Y
AU - Casado-Pelaez, Marta
AU - Herrero-Molinero, P
AU - Brujas, C
AU - Castelluccio, Noemi
AU - Miranda, Jessica Gonzalez
AU - Iglesias, A
AU - Marruecos, L
AU - Ruiz-Herguido, C
AU - Esteller, M.
AU - Mereu, Elisabetta
AU - Lacaud, Georges
AU - ESPINOSA, LLUIS
AU - BIGAS, A.
PY - 2024/6/1
Y1 - 2024/6/1
N2 - 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 IκBα (Nfkbia, the inhibitor of NF-κB) as a critical regulator of HSC proliferation throughout development. IκBα balances retinoic acid signaling levels together with the epigenetic silencer, PRC2, specifically in HSCs. Loss of IκBα decreases proliferation of HSC and induces a dormancy related gene expression signature instead. Also, IκBα 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 IκBα deficient HSCs. Overall, we show that the proliferation index in the developing HSCs is regulated by a IκBα-PRC2 axis, which controls retinoic acid signaling.
AB - 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 IκBα (Nfkbia, the inhibitor of NF-κB) as a critical regulator of HSC proliferation throughout development. IκBα balances retinoic acid signaling levels together with the epigenetic silencer, PRC2, specifically in HSCs. Loss of IκBα decreases proliferation of HSC and induces a dormancy related gene expression signature instead. Also, IκBα 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 IκBα deficient HSCs. Overall, we show that the proliferation index in the developing HSCs is regulated by a IκBα-PRC2 axis, which controls retinoic acid signaling.
UR - https://europepmc.org/articles/PMC11144194
U2 - 10.1038/s41467-024-48854-5
DO - 10.1038/s41467-024-48854-5
M3 - Article
C2 - 38824124
SN - 2041-1723
JO - Nature Communications
JF - Nature Communications
ER -
SDG 3 Good Health and Well-being