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| Home > Articles > Published articles > IκBα controls dormancy in hematopoietic stem cells via retinoic acid during embryonic development |
(Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (University of Manchester) (University of Manchester) (Institut Hospital del Mar d'Investigacions Mèdiques) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Universitair Ziekenhuis Gent) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Hospital del Mar d'Investigacions Mèdiques) (Universitat de Barcelona. Departament de Ciències Fisiològiques) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (University of Manchester) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)| Date: | 2024 |
| 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. |
| Grants: | Agencia Estatal de Investigación PID2019-104695RB-I00 Agencia Estatal de Investigación PDC2021-120817-I00 Agencia Estatal de Investigación SAF2016-75613-R Generalitat de Catalunya SLT002/16/00299 |
| Note: | IGTP |
| Note: | We thank all members of Espinosa and Bigas laboratories for helpful discussions and technical support. We also thank the animal facility, FACS facility, and genomic facility of the PRBB, CRUK Manchester Institute, and the single-cell Unit of the IJC for their technical support. This work was funded by grants from SAF2016-75613-R, PID2019-104695RB-I00, and PDC2021-120817-I00 from Agencia Estatal de Investigaci\u00F3n (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). |
| Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Language: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Subject: | Animals ; Cell Proliferation ; Embryonic Development ; Female ; Gene Expression Regulation, Developmental ; Hematopoietic Stem Cells ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; NF-KappaB Inhibitor alpha ; Polycomb Repressive Complex 2 ; Signal Transduction ; Tretinoin |
| Published in: | Nature communications, Vol. 15 Núm. 1 (december 2024) , p. 4673, ISSN 2041-1723 |
