tRNA m1A modification regulate hematopoietic stem cell maintenance via mTORC1 signaling [scRNA-seq]
Hematopoietic stem cells (HSCs) have some unique physiological adaptations to maintain blood cell production and deal with stress responses throughout life. To maintain such adaptations, HSCs are particularly dependent on maintaining a tightly controlled protein translation rate. However, how HSCs fine tune protein translation has not been fully described. In this study, we report the role of TRMT6 in regulating HSC function in adult hematopoiesis. Trmt6-null mice became moribund due to hematopoietic failure with pancytopenia in the blood and bone marrow 4 to 8 weeks after Trmt6 deletion. Trmt6-deleted bone marrow cells failed to repopulate hemoablated recipients in competitive transplantation experiments. Loss of TRMT6 resulted in an abnormally high rate of recruitment of quiescent hematopoietic stem cells (HSCs) into the cell cycle. Cycling HSCs produced progenitors at the expense of self-renewal, which led to the exhaustion of the HSC pool. Mechanistically, mTORC1 signaling pathway was highly upregulated in HSC-enriched cell populations after Trmt6 deletion by single cell RNA-seq analysis. Furthermore, TRMT6 was required for tRNA m1A modification required for HSC quiescence and self-renewal. Our data indicate that TRMT6 promotes the expression of TSC1, fine-tuning mTORC1 signaling level which is essential for HSC maintenance and self-renewal in adult hematopoiesis. Overall design: single-cell RNA-sequencing (scRNA-seq) analysis of total LSK (Lin- Sca-1+ c-Kit+ ) hematopoietic stem and progenitor cells (HSPCs) isolated from the bone marrow of young adult (3-month-old) wild-type and hematopoietic-specific Trmt6-knockout mice.