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    • tRNA m1A58, Nrf1 and HSPC Apoptosis

    2026-09-28

    Research Question

    During zebrafish embryonic development, do TRMT61A/TRMT6-mediated tRNA m1A58 modifications help hemogenic endothelial cells produce hematopoietic stem and progenitor cells (HSPCs) by controlling translation? The authors focused on whether reduced Nrf1 translation and altered cell survival could explain the HSPC phenotype in the aorta-gonad-mesonephros (AGM) region.

    Study Design and Methods

    The study combined loss-of-function and rescue experiments in zebrafish embryos. The authors depleted trmt61a or trmt6 with morpholinos, examined trmt61a mutant and catalytic-dead embryos, and used mRNA rescue experiments to test gene specificity and the importance of Trmt61a catalytic activity. They assessed HSPC development using marker expression, including runx1 and cmyb, and imaging of endothelial and emerging HSPC populations.

    The central mechanistic evidence came from measurements of tRNA modification and translation: tRNA-m1A sequencing assessed modification changes, ribosome profiling compared translation efficiency, and polysome profiling with qPCR examined nrf1 mRNA association with translating ribosomes. A synonymous codon-switch nrf1 construct tested whether changing codon usage could restore Nrf1 protein and HSPC production. RNA sequencing and proteomics provided broader context for gene-expression and protein changes; these were supporting analyses rather than direct tests of cell-death mechanism.

    For the cell-death question, the authors used TUNEL staining in the ventral dorsal aorta and knocked down p53 to test whether reducing p53 activity changed both the apoptotic signal and HSPC outcome. Mitochondrial content measurements and nrf1 loss-of-function experiments supported the proposed link between Nrf1 and mitochondrial homeostasis.

    Main Findings

    Reported findings: trmt61a depletion and maternal-zygotic trmt61a mutation reduced HSPC markers and HSPC numbers. The catalytic-dead Trmt61a variant also impaired HSPC development, while endothelial expression of wild-type, but not catalytic-dead, Trmt61a rescued the phenotype. The authors report that loss of Trmt61a reduced tRNA m1A58 modification and overall translation efficiency. Although nrf1 mRNA was not reduced in the polysome analysis, its association with polysomes fell. A synonymous codon-modified nrf1 construct restored Nrf1 protein and significantly rescued HSPC development, whereas the wild-type construct did not provide comparable functional rescue.

    The study also reports reduced mitochondrial content and changes in mitochondrial-related measurements after trmt61a or nrf1 loss. nrf1-deficient embryos showed reduced HSPC markers and increased apoptotic signal, resembling aspects of the trmt61a phenotype. These results support the authors’ model that Trmt61a-dependent Nrf1 translation contributes to mitochondrial homeostasis during HSPC emergence.

    Cell-death evidence and interpretation: TUNEL-positive endothelial cells increased in the AGM region of trmt61a-deficient embryos. p53 knockdown reduced the TUNEL signal and restored HSPC production. This intervention provides evidence that p53-dependent apoptosis contributes to the developmental phenotype; it is stronger than an association based only on cell-survival measurements. The study’s findings concern apoptosis, not ferroptosis: the reported experiments do not establish a ferroptosis pathway or provide a ferroptosis-specific rescue. RNA-sequencing enrichment of apoptosis-related pathways is supporting evidence, not by itself proof of a particular execution mechanism.

    The authors therefore interpret the results as a pathway in which reduced tRNA m1A58 compromises Nrf1 translation, disrupts mitochondrial homeostasis, and promotes p53-dependent apoptosis that limits HSPC production. The rescue and translation experiments support key links in this model, while they do not establish that every downstream effect is mediated exclusively through mitochondria.

    Limitations

    • The experiments address zebrafish embryonic hematopoiesis. They do not establish that the same regulatory mechanism operates in other species, adult HSCs, or clinical settings.
    • The study supports p53-dependent apoptosis through TUNEL and p53-knockdown rescue, but the reported work does not determine whether apoptosis is caspase-dependent or caspase-independent. Caspase activity or caspase-dependence experiments are not reported in the supplied text.
    • No ferroptosis-specific pathway evidence or rescue is reported, so the findings should not be described as ferroptosis.
    • Nrf1 and mitochondrial results support the proposed connection, but the reported experiments do not include a mitochondria-specific rescue that isolates mitochondrial dysfunction as the sole intermediate between altered Nrf1 translation and apoptosis.
    • The RNA-sequencing and proteomics analyses report two biological replicates; replicate numbers vary across other experiments. This is relevant when weighing the breadth of the discovery analyses.

    Source

    Dong Z, Li P, Liu M, et al. tRNA m1A modification ensures HSPC production via modulating Nrf1 translation in zebrafish. EMBO Reports. https://doi.org/10.1038/s44319-026-00805-5.