Nuclear DEK preserves hematopoietic stem cells potential via NCoR1/HDAC3-Akt1/2-mTOR axis.
Nuclear DEK preserves hematopoietic stem cells potential via NCoR1/HDAC3-Akt1/2-mTOR axis.
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DOI：
10.1084/jem.20201974
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发表时间：
2021-05-03
期刊：
影响因子：
--
通讯作者：
Hou Y
中科院分区：
文献类型：
--
作者：
Chen Z;Huo D;Li L;Liu Z;Li Z;Xu S;Huang Y;Wu W;Zhou C;Liu Y;Kuang M;Wu F;Li H;Qian P;Song G;Wu X;Chen J;Hou Y
本研究表明，核内DEK调控HSC的静止和代谢动态平衡，并保护HSC的潜能。机制上，DEK通过诱导H3K27的脱乙酰化抑制染色质的可及性，控制包括Akt1/2在内的基因表达。癌基因DEK被发现与NUP214基因融合，产生癌蛋白DEK-NUP214，在患者中诱导急性髓系白血病(AML)，并分泌DEK蛋白作为造血细胞因子调节造血；然而，核DEK在造血干细胞(HSCs)中的内在作用仍很不清楚。在这里，我们发现缺乏DEK的HSCs在长期自我更新能力方面表现出缺陷，最终导致造血功能受损。DEK缺乏减少了HSCs的静止，加速了线粒体的代谢，部分依赖于激活mTOR信号。在分子水平上，DEK招募辅阻遏子NCoR1来抑制组蛋白3在赖氨酸27(H3K27ac)的乙酰化，并限制HSCs染色质的可及性，控制静止相关基因(如Akt1/2、Ccnb2和p21)的表达。抑制mTOR活性在很大程度上恢复了DEK-CKO造血干细胞的维持和潜能。这些发现突出了核DEK在保持HSC潜能方面的关键作用，揭示了染色质重构体和HSC动态平衡之间的新联系，并具有临床意义。
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. 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.
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影响因子：
5.2
作者：
Broxmeyer, Hal E.;Mor-Vaknin, Nirit;Kappes, Ferdinand;Legendre, Maureen;Saha, Anjan K.;Ou, Xuan;O'Leary, Heather;Capitano, Maegan;Cooper, Scott;Markovitz, David M.
通讯作者：
Markovitz, David M.
影响因子：
23.9
作者：
Magee, Jeffrey A.;Ikenoue, Tsuneo;Nakada, Daisuke;Lee, Jae Y.;Guan, Kun-Liang;Morrison, Sean J.
通讯作者：
Morrison, Sean J.
影响因子：
21.3
作者：
Liu, Lu;Zhao, Meiling;Li, Qing
通讯作者：
Li, Qing
影响因子：
5.3
作者：
Kappes, F;Scholten, I;Waldmann, T
通讯作者：
Waldmann, T
影响因子：
16.6
作者：
Kaya-Okur, Hatice S.;Wu, Steven J.;Henikoff, Steven
通讯作者：
Henikoff, Steven