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

• Published in: The Journal of experimental medicine Vol. 218; no. 5
• Main Authors: Chen, Zhe, Huo, Dawei, Li, Lei, Liu, Zhilong, Li, Zhigang, Xu, Shuangnian, Huang, Yongxiu, Wu, Weiru, Zhou, Chengfang, Liu, Yuanyuan, Kuang, Mei, Wu, Feng, Li, Hui, Qian, Pengxu, Song, Guanbin, Wu, Xudong, Chen, Jieping, Hou, Yu
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 03-05-2021
• Subjects: Animals; Cell Self Renewal - genetics; Cells, Cultured; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Hematopoiesis; Hematopoiesis - genetics; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Histone Deacetylases - metabolism; Histones - metabolism; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Nuclear Receptor Co-Repressor 1 - metabolism; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Poly-ADP-Ribose Binding Proteins - genetics; Poly-ADP-Ribose Binding Proteins - metabolism; Proteins - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; TOR Serine-Threonine Kinases - metabolism
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20201974

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.