Wang Hui, Zhang Zhaoru, Han Chenxi, Jiang Penglei, Xu Jiayue, Han Yingli, Huang Deyu, Li Jian, Zhou Jie, Durnin Michael, Chen Shiyuan, Liu Yaxin, Sheng Jinghao, Cao Jie, Liu Jianzhao, Liu Bing, Yu Jia, Wang Fang, Qian Pengxu
Bone Marrow Transplantation Center of the First Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine, State Key Laboratory of Experimental Hematology, Hangzhou, China.
Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China.
Nat Cell Biol. 2025 Feb;27(2):246-261. doi: 10.1038/s41556-024-01593-7. Epub 2025 Jan 31.
Haematopoietic stem cells (HSCs) self-renew and differentiate to replenish the pool of blood cells, which require a low but finely tuned protein synthesis rate. Nonetheless, the translatome landscape in HSCs and how the translation machinery orchestrates HSC self-renewal remain largely elusive. Here we perform ultra-low-input Ribo-seq in HSCs, progenitor and lineage cells, and reveal HSC-specific translated genes involved in rRNA processing. We systematically profile small nucleolar RNAs (snoRNAs) and uncover an indispensable role of the SNORD113-114 cluster in regulating HSC self-renewal. Maternal knockout (Mat-KO) of this cluster substantially impairs HSC self-renewal, whereas loss of the paternal allele shows no obvious phenotype. Mechanistically, Mat-KO results in dysregulation of translation machinery (rRNA 2'-O-Me modifications, pre-rRNA processing, 60S ribosome assembly and translation) and induces nucleolar stress in HSCs, which exempts p53 from Mdm2-mediated proteasomal degradation and leads to apoptosis. Collectively, our study provides a promising facet to our understanding of snoRNA-mediated regulation in HSC homeostasis.
造血干细胞（HSCs）自我更新并分化以补充血细胞池，这需要低但精确调节的蛋白质合成速率。尽管如此，造血干细胞中的翻译组图谱以及翻译机制如何协调造血干细胞自我更新在很大程度上仍不清楚。在这里，我们对造血干细胞、祖细胞和谱系细胞进行超低输入核糖体测序（Ribo-seq），并揭示参与核糖体RNA（rRNA）加工的造血干细胞特异性翻译基因。我们系统地分析了小核仁RNA（snoRNAs），并发现SNORD113-114簇在调节造血干细胞自我更新中具有不可或缺的作用。该簇的母源敲除（Mat-KO）显著损害造血干细胞自我更新，而父源等位基因缺失则无明显表型。从机制上讲，母源敲除导致翻译机制失调（rRNA 2'-O-甲基化修饰、前体rRNA加工、60S核糖体组装和翻译），并在造血干细胞中诱导核仁应激，这使p53免于Mdm2介导的蛋白酶体降解并导致细胞凋亡。总的来说，我们的研究为理解snoRNA介导的造血干细胞稳态调节提供了一个有前景的方面。
