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Nuclear DEK preserves hematopoietic stem cells potential via NCoR1/HDAC3-Akt1/2-mTOR axis
- Source :
- The Journal of Experimental Medicine
- Publication Year :
- 2021
- Publisher :
- Rockefeller University Press, 2021.
-
Abstract
- This study demonstrates that nuclear DEK governs quiescence and metabolic homeostasis of HSC and preserves HSC potential. Mechanistically, DEK dampens chromatin accessibility in HSC by inducing deacetylation of H3K27 and governs gene expression, including Akt1/2.<br />The oncogene DEK is found fused with the NUP214 gene creating oncoprotein DEK-NUP214 that induces acute myeloid leukemia (AML) in patients, and secreted DEK protein functions as a hematopoietic cytokine to regulate hematopoiesis; however, the intrinsic role of nuclear DEK in hematopoietic stem cells (HSCs) remains largely unknown. Here, we show that HSCs lacking DEK display defects in long-term self-renew capacity, eventually resulting in impaired hematopoiesis. DEK deficiency reduces quiescence and accelerates mitochondrial metabolism in HSCs, in part, dependent upon activating mTOR signaling. At the molecular level, DEK recruits the corepressor NCoR1 to repress acetylation of histone 3 at lysine 27 (H3K27ac) and restricts the chromatin accessibility of HSCs, governing the expression of quiescence-associated genes (e.g., Akt1/2, Ccnb2, and p21). Inhibition of mTOR activity largely restores the maintenance and potential of Dek-cKO HSCs. These findings highlight the crucial role of nuclear DEK in preserving HSC potential, uncovering a new link between chromatin remodelers and HSC homeostasis, and have clinical implications.
- Subjects :
- 0301 basic medicine
Immunology
Mice, Transgenic
Article
Histone Deacetylases
Histones
03 medical and health sciences
0302 clinical medicine
Immunology and Allergy
Animals
Humans
Nuclear Receptor Co-Repressor 1
Cell Self Renewal
Poly-ADP-Ribose Binding Proteins
PI3K/AKT/mTOR pathway
Nuclear receptor co-repressor 1
Cells, Cultured
Mice, Knockout
Oncogene Proteins
biology
TOR Serine-Threonine Kinases
Nuclear Proteins
Proteins
hemic and immune systems
HDAC3
Hematopoietic Stem Cells
Chromatin
Cell biology
Hematopoiesis
DNA-Binding Proteins
Mice, Inbred C57BL
Haematopoiesis
stomatognathic diseases
030104 developmental biology
Histone
030220 oncology & carcinogenesis
biology.protein
Stem cell
Corepressor
Proto-Oncogene Proteins c-akt
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 15409538 and 00221007
- Volume :
- 218
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- The Journal of Experimental Medicine
- Accession number :
- edsair.doi.dedup.....80236f419ae7013d1b7c6b18c0e445f4