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

Autor: Thambyrajah R; Program in Cancer Research, Hospital del Mar Research Institute, Barcelona, Spain. roshanathambyrajah@gmail.com.; Josep Carreras Leukemia Research Institute, Barcelona, Spain. roshanathambyrajah@gmail.com., Maqueda M; Program in Cancer Research, Hospital del Mar Research Institute, Barcelona, Spain.; Josep Carreras Leukemia Research Institute, Barcelona, Spain.; Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain., Fadlullah MZ; Cancer Research UK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK., Proffitt M; Program in Cancer Research, Hospital del Mar Research Institute, Barcelona, Spain., Neo WH; Cancer Research UK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK., Guillén Y; Program in Cancer Research, Hospital del Mar Research Institute, Barcelona, Spain., Casado-Pelaez M; Josep Carreras Leukemia Research Institute, Barcelona, Spain., Herrero-Molinero P; Program in Cancer Research, Hospital del Mar Research Institute, Barcelona, Spain., Brujas C; Program in Cancer Research, Hospital del Mar Research Institute, Barcelona, Spain., Castelluccio N; Program in Cancer Research, Hospital del Mar Research Institute, Barcelona, Spain.; Ghent University Hospital, Ghent, Belgium., González J; Program in Cancer Research, Hospital del Mar Research Institute, Barcelona, Spain.; Josep Carreras Leukemia Research Institute, Barcelona, Spain.; Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain., Iglesias A; Program in Cancer Research, Hospital del Mar Research Institute, Barcelona, Spain.; Josep Carreras Leukemia Research Institute, Barcelona, Spain.; Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain., Marruecos L; Program in Cancer Research, Hospital del Mar Research Institute, Barcelona, Spain., Ruiz-Herguido C; Program in Cancer Research, Hospital del Mar Research Institute, Barcelona, Spain., Esteller M; Josep Carreras Leukemia Research Institute, Barcelona, Spain.; Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain.; Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.; Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Catalonia, Spain., Mereu E; Josep Carreras Leukemia Research Institute, Barcelona, Spain., Lacaud G; Cancer Research UK Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK., Espinosa L; Program in Cancer Research, Hospital del Mar Research Institute, Barcelona, Spain.; Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain., Bigas A; Program in Cancer Research, Hospital del Mar Research Institute, Barcelona, Spain. abigas@imim.es.; Josep Carreras Leukemia Research Institute, Barcelona, Spain. abigas@imim.es.; Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain. abigas@imim.es.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jun 01; Vol. 15 (1), pp. 4673. Date of Electronic Publication: 2024 Jun 01.
DOI: 10.1038/s41467-024-48854-5
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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