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