The ac4C acetyltransferase Nat10 promotes RNA stability to support hematopoietic stem cell fate [RNA-seq-32D]

The control of gene expression program is believed to underlie hematopoietic stem cell (HSC) homeostasis. However, a comprehensive molecular understanding of the RNA level regulation is currently lacking. Here we provide evidence that the HSC-associated transcripts have longer 3’UTRs and more enriched AU-rich elements (AREs), which were recognized by Nat10. Nat10 is highly expressed in HSC and its deficiency disrupts HSC self-renewal and long-term maintenance. In contrast to current model that invoke ac4C modification to mediate downstream effects, we find Nat10 recruits ribosomes to mRNA 3’UTRs and protects them from degradation by ZFP36-CNOT RNA decay complex. Nat10 depletion leads to reduction of mRNA hail-life, and both wild-type and catalytically inactive Nat10 promote the stability of mRNA with AREs. We present a model that Nat10 regulates mRNA stability as an ARE-binding protein rather than ac4C writer in HSC, a mechanism is required for hematopoietic homeostasis, highlighting the importance of transcript-specific characteristics determining the contribution of Nat10 in HSC fate.