tRNA m1A modification ensures HSPC production via modulating Nrf1 translation in zebrafish

Abstract During embryogenesis, nascent hematopoietic stem and progenitor cells (HSPCs) arise from hemogenic endothelium via endothelial-to-hematopoietic transition (EHT). While this process is orchestrated by multiple intrinsic factors, the role of tRNA-mediated translational control during EHT remains poorly understood. Here, we identify tRNA m 1 A58 as a predominant tRNA modification in specifying HSPC fate in zebrafish embryos. Depletion of trmt61a compromises HSPC production in the aorta-gonad-mesonephros (AGM) region, accompanied by attenuated tRNA m 1 A58 levels and evident p53 -dependent apoptosis. Mechanistically, Trmt61a-mediated tRNA m 1 A58 modification enhances translation efficiency of nuclear respiratory factor 1 (Nrf1), a key regulator of mitochondrial biogenesis. Consequently, trmt61a deficiency leads to mitochondrial dysfunction and compromises cell survival, ultimately impairing HSPC production. Our findings establish that tRNA m 1 A58 modification is essential for HSPC generation by supporting translation efficiency, providing new insights into improved strategies for in vitro HSPC induction.