tRNA-m1A Modification Safeguards Fetal Liver HSPCs from DNA Damage via Maintaining Iron Homeostasis

Hematopoietic stem and progenitor cell (HSPC) development requires finely tuned gene expression programs, yet the role of tRNA modifications in this process remains largely unknown. Here, we uncover the essential function of the tRNA methyltransferase Trmt61a in sustaining fetal liver (FL) HSPCs through N1-methyladenosine (m¹A) deposition. Ribosome profiling revealed globally declined translation efficiency due to translational blockage upon Trmt61a loss in HSPCs, notably the transferrin receptor (Tfrc). Mechanistically, m1A reduction caused ribosomal stalling at Arginine-CGG codons in Tfrc mRNA, thus suppressing Tfrc synthesis and leading to intra-cellular iron depletion. This iron deficiency triggered DNA damage and compromised HSPC survival. Our work elucidates an epitranscriptomic pathway, the Trmt61a-m¹A-Tfrc axis, that safeguards HSPC integrity by linking tRNA modification to iron homeostasis and preventing DNA damage, providing mechanistic and therapeutic insights into hematopoietic disorders.