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Nuclear DEK preserves hematopoietic stem cells potential via NCoR1/HDAC3-Akt1/2-mTOR axis

Authors :
Shuangnian Xu
Yongxiu Huang
Yuanyuan Liu
Dawei Huo
Guanbin Song
Feng Wu
Weiru Wu
Yu Hou
Chengfang Zhou
Pengxu Qian
Hui Li
Mei Kuang
Xudong Wu
Zhigang Li
Zhe Chen
Jieping Chen
Lei Li
Zhilong Liu
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.

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