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

Roshana Thambyrajah (), Maria Maqueda, Muhammad Zaki Fadlullah, Martin Proffitt, Wen Hao Neo, Yolanda Guillén, Marta Casado-Pelaez, Patricia Herrero-Molinero, Carla Brujas, Noemi Castelluccio, Jessica González, Arnau Iglesias, Laura Marruecos, Cristina Ruiz-Herguido, Manel Esteller, Elisabetta Mereu, Georges Lacaud, Lluis Espinosa and Anna Bigas ()
Additional contact information
Roshana Thambyrajah: Hospital del Mar Research Institute
Maria Maqueda: Hospital del Mar Research Institute
Muhammad Zaki Fadlullah: The University of Manchester
Martin Proffitt: Hospital del Mar Research Institute
Wen Hao Neo: The University of Manchester
Yolanda Guillén: Hospital del Mar Research Institute
Marta Casado-Pelaez: Josep Carreras Leukemia Research Institute
Patricia Herrero-Molinero: Hospital del Mar Research Institute
Carla Brujas: Hospital del Mar Research Institute
Noemi Castelluccio: Hospital del Mar Research Institute
Jessica González: Hospital del Mar Research Institute
Arnau Iglesias: Hospital del Mar Research Institute
Laura Marruecos: Hospital del Mar Research Institute
Cristina Ruiz-Herguido: Hospital del Mar Research Institute
Manel Esteller: Josep Carreras Leukemia Research Institute
Elisabetta Mereu: Josep Carreras Leukemia Research Institute
Georges Lacaud: The University of Manchester
Lluis Espinosa: Hospital del Mar Research Institute
Anna Bigas: Hospital del Mar Research Institute

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-48854-5

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