Zfp521 is essential for the quiescence and maintenance of adult hematopoietic stem cells under stress.
Zfp521 is essential for the quiescence and maintenance of adult hematopoietic stem cells under stress.
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Zfp521 对于成体造血干细胞在压力下的静止和维持至关重要。
DOI：
10.1016/j.isci.2021.102039
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发表时间：
2021-02-19
期刊：
影响因子：
5.8
通讯作者：
Hou Y
中科院分区：
文献类型：
--
作者：
Li Z;Fu X;Wu W;Liu Z;Chen Z;Zhou C;Liu Y;Kuang M;Sun F;Xiao F;Huang Y;Zhang X;Fan S;Huang X;Zheng G;Chen J;Hou Y
锌指蛋白521（Zfp 521）是一种富含造血干细胞（HSC）的转录因子，参与胎肝HSC的自我更新和分化。然而，它在成人造血中的作用仍然难以捉摸。在此，我们发现Zfp 521缺失在稳态条件下不抑制成体造血。相比之下，Zfp 521-null嵌合体小鼠显示与增加的凋亡和静止丧失相关的HSC和造血祖细胞的池大小显著降低。竞争性系列移植试验表明，Zfp 521调节HSC自我更新和分化再生应激。从机制上讲，Zfp 521通过增加其启动子中的H3 K9 ac和降低H3 K9 me 3水平来转录抑制Rela表达。Rela基因的敲除可抑制应激状态下Zfp 521基因敲除的HSC中NF-κB通路的过度活化，并逆转应激状态下Zfp 521基因敲除的HSC中NF-κ B通路的失稳。因此，我们的研究结果揭示了Zfp 521作为至少部分通过控制Rela表达介导的成体造血中HSC的静止和自我更新的关键调节剂的先前未被认识的作用。Zfp 521缺失在稳态条件下不抑制成体造血Zfp 521调节HSC在应激下的静止和维持Zfp 521缺乏影响HSC中的NF-κB通路敲低Rela逆转Zfp 521缺失HSC在应激下的静止丧失分子生物学;细胞生物学;干细胞研究;转录组学
Zinc finger protein 521 (Zfp521), a quiescent hematopoietic stem cell (HSC)-enriched transcription factor, is involved in the self-renewal and differentiation of fetal liver HSC. However, its role in adult hematopoiesis remains elusive. Here, we found that Zfp521 deletion did not inhibit adult hematopoiesis under homeostatic conditions. In contrast, Zfp521-null chimeric mice showed significantly reduced pool size of HSC and hematopoietic progenitor cells associated with increased apoptosis and loss of quiescence. Competitive serial transplantation assays revealed that Zfp521 regulates HSC self-renewal and differentiation under regenerative stress. Mechanistically, Zfp521 transcriptionally repressed Rela expression by increasing H3K9ac and decreasing H3K9me3 levels in its promoter. Knockdown of Rela inhibited the hyper-activated NF-κB pathway and reversed the loss of quiescence in Zfp521-null HSC under stress. Thus, our results reveal a previously unrecognized role for Zfp521 as critical regulator of quiescence and self-renewal of HSC in adult hematopoiesis mediated at least partly by controlling Rela expression. Zfp521 deletion does not inhibit adult hematopoiesis under homeostatic conditions Zfp521 regulates the quiescence and maintenance of HSC under stress Zfp521 deficiency affects the NF-κB pathway in HSC Knockdown of Rela reverses the loss of quiescence in Zfp521-null HSC under stress Molecular Biology; Cell Biology; Stem Cell Research; Transcriptomics
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影响因子：
11.8
作者：
Correa, Diego;Hesse, Eric;Seriwatanachai, Dutmanee;Kiviranta, Riku;Saito, Hiroaki;Yamana, Kei;Neff, Lynn;Atfi, Azeddine;Coillard, Lucie;Sitara, Despina;Maeda, Yukiko;Warming, Soren;Jenkins, Nancy A.;Copeland, Neal G.;Horne, William C.;Lanske, Beate;Baron, Roland
通讯作者：
Baron, Roland
影响因子：
64.5
作者：
Adolfsson, J;Månsson, R;Jacobsen, SEW
通讯作者：
Jacobsen, SEW
影响因子：
4.8
作者：
Lin, AC;Roche, AE;Svensson, EC
通讯作者：
Svensson, EC
影响因子：
2
作者：
Behrouznezhad F;Ejeian F;Emadi-Baygi M;Nikpour P;Nasr-Esfahani MH
通讯作者：
Nasr-Esfahani MH
影响因子：
30.5
作者：
Boone, DL;Turer, EE;Ma, A
通讯作者：
Ma, A