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

Thambyrajah, Roshana; Maqueda, Maria; Fadlullah, Zaki; Proffitt, Martin; Neo, Wen Hao; Guillén, Yolanda; Casado-Peláez, Marta; Herrero-Molinero, Patricia; Brujas, Carla; Castelluccio, Noemi; González, Jessica; Iglesias, Arnau; Marruecos, Laura; Ruiz-Herguido, Cristina; Esteller, Manel; Mereu, Elisabetta; Lacaud, Georges; Espinosa Blay, Lluís; Bigas Salvans, Anna

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

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dc.contributor.author Thambyrajah, Roshana
dc.contributor.author Maqueda, Maria
dc.contributor.author Fadlullah, Zaki
dc.contributor.author Proffitt, Martin
dc.contributor.author Neo, Wen Hao
dc.contributor.author Guillén, Yolanda
dc.contributor.author Casado-Peláez, Marta
dc.contributor.author Herrero-Molinero, Patricia
dc.contributor.author Brujas, Carla
dc.contributor.author Castelluccio, Noemi
dc.contributor.author González, Jessica
dc.contributor.author Iglesias, Arnau
dc.contributor.author Marruecos, Laura
dc.contributor.author Ruiz-Herguido, Cristina
dc.contributor.author Esteller, Manel
dc.contributor.author Mereu, Elisabetta
dc.contributor.author Lacaud, Georges
dc.contributor.author Espinosa Blay, Lluís
dc.contributor.author Bigas Salvans, Anna
dc.date.accessioned 2025-07-08T06:35:23Z
dc.date.available 2025-07-08T06:35:23Z
dc.date.issued 2024
dc.description.abstract 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.
dc.description.sponsorship This work was funded by grants from SAF2016-75613-R, PID2019-104695RB-I00, and PDC2021-120817-I00 from Agencia Estatal de Investigación (AEI) and SLT002/16/00299 from Department of Health, Generalitat de Catalunya. The work in G.L. laboratory is supported by Blood Cancer UK (19014) and Cancer Research UK Manchester Institute Core Grant (C5759/A27412). R.T. is a recipient of BP2016(00021) and BP/MSCA 2018(00034) fellowship programs from Generalitat de Catalunya/MSCA. M.M. is a recipient of a grant from the Instituto Carlos III, grant number CA22/00011 (co-funded by the European Social Fund Plus, ESF+, and by the European Union).
dc.format.mimetype application/pdf
dc.identifier.citation Thambyrajah 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/s41467-024-48854-5
dc.identifier.doi http://dx.doi.org/10.1038/s41467-024-48854-5
dc.identifier.issn 2041-1723
dc.identifier.uri http://hdl.handle.net/10230/70856
dc.language.iso eng
dc.publisher Nature Research
dc.relation.ispartof Nat Commun. 2024 Jun 1;15(1):4673
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2016-75613-R
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-104695RB-I00
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PDC2021-120817-I00
dc.rights © 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/.
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.keyword Haematopoiesis
dc.subject.keyword Haematopoietic stem cells
dc.subject.keyword Histone post-translational modifications
dc.title IκBα controls dormancy in hematopoietic stem cells via retinoic acid during embryonic development
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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