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<p>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.</p>

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SNORD113–114 cluster maintains haematopoietic stem cell self-renewal via orchestrating the translation machinery

  • 期刊论文

  • 发表日期：

    2025年1月31日

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  • Hui Wang,
  • Zhaoru Zhang,
  • Chenxi Han,
  • Penglei Jiang,
  • Jiayue Xu,
  • Yingli Han,
  • Deyu Huang,
  • Jian Li,
  • Jie Zhou,
  • Michael Durnin,
  • Shiyuan Chen,
  • Yaxin Liu,
  • Jinghao Sheng,
  • Jie Cao,
  • Jianzhao Liu,
  • Bing Liu,
  • Jia Yu,
  • Fang Wang,
  • Pengxu Qian

摘要

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.