Thambyrajah, RoshanaMaqueda, MariaFadlullah, ZakiProffitt, MartinNeo, Wen HaoGuillén, YolandaCasado-Peláez, MartaHerrero-Molinero, PatriciaBrujas, CarlaCastelluccio, NoemiGonzález, JessicaIglesias, ArnauMarruecos, LauraRuiz-Herguido, CristinaEsteller, ManelMereu, ElisabettaLacaud, GeorgesEspinosa Blay, LluísBigas Salvans, Anna2025-07-082025-07-082024Thambyrajah R, Maqueda M, Fadlullah MZ, Proffitt M, Neo WH, Guillén Y, et al. IκBα controls dormancy in hematopoietic stem cells via retinoic acid during embryonic development. Nat Commun. 2024 Jun 1;15(1):4673. DOI: 10.1038/s41467-024-48854-52041-1723http://hdl.handle.net/10230/70856Recent 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.application/pdfeng© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-024-48854-5HaematopoiesisHaematopoietic stem cellsHistone post-translational modificationsinfo:eu-repo/semantics/openAccess