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<p>Haematopoietic stem cells (HSCs) represent a well-established system for studying stem cell maintenance. While RNA regulators have been reported in HSCs, a systematic characterization and how they define transcript fate remains outstanding. Here we profile RNA characteristics of HSC-essential genes and uncover a notable feature in both human and mouse: they have extended 3′ untranslated regions specifically enriched with AU-rich elements (AREs). These AREs are crucial for the expression of HSC genes, primarily through NAT10, which stabilizes their mRNAs. Notably, <i>Nat10</i> deficiency markedly disrupts HSCs self-renewal and long-term reconstitution capacity. Mechanistically, NAT10 recruits ribosomes to the 3′ untranslated region AREs of HSC-essential mRNAs, sheltering them from degradation—an effect independent of NAT10’s ac<sup>4</sup>C catalytic activity. Moreover, <i>NAT10</i> dysregulations were associated with multiple human haematological malignancies. Collectively, our findings uncover a specific mechanism of RNA turnover control mediated by specific RNA ARE motifs and identify a non-catalytic role of NAT10 in maintaining HSC homeostasis.</p>

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NAT10 maintains stem cell homeostasis by mitigating mRNA decay through an ac4C-independent mechanism

  • 期刊论文

  • 发表日期：

    2026年5月4日

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  • Weiqian Li,
  • Yue Huo,
  • Zhaoru Zhang,
  • Yiyang Liu,
  • Xinyue Qian,
  • Jia Ouyang,
  • Rao Gu,
  • Chenxi Han,
  • Shuo Li,
  • Rui Su,
  • Jia Yu,
  • Pengxu Qian,
  • Fang Wang

摘要

Haematopoietic stem cells (HSCs) represent a well-established system for studying stem cell maintenance. While RNA regulators have been reported in HSCs, a systematic characterization and how they define transcript fate remains outstanding. Here we profile RNA characteristics of HSC-essential genes and uncover a notable feature in both human and mouse: they have extended 3′ untranslated regions specifically enriched with AU-rich elements (AREs). These AREs are crucial for the expression of HSC genes, primarily through NAT10, which stabilizes their mRNAs. Notably, Nat10 deficiency markedly disrupts HSCs self-renewal and long-term reconstitution capacity. Mechanistically, NAT10 recruits ribosomes to the 3′ untranslated region AREs of HSC-essential mRNAs, sheltering them from degradation—an effect independent of NAT10’s ac4C catalytic activity. Moreover, NAT10 dysregulations were associated with multiple human haematological malignancies. Collectively, our findings uncover a specific mechanism of RNA turnover control mediated by specific RNA ARE motifs and identify a non-catalytic role of NAT10 in maintaining HSC homeostasis.