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

Area of Science:

• Molecular Biology
• Epigenetics
• Hematopoiesis

Background:

• Hematopoietic stem and progenitor cell (HSPC) development relies on precise gene expression.
• The role of tRNA modifications in HSPC development is largely unexplored.

Purpose of the Study:

• To investigate the function of tRNA methyltransferase Trmt61a in fetal liver (FL) HSPCs.
• To elucidate the molecular mechanisms by which Trmt61a supports HSPC integrity.

Main Methods:

• Utilized ribosome profiling to assess translation efficiency in HSPCs.
• Analyzed the impact of Trmt61a loss on gene expression and cellular iron levels.
• Investigated the link between tRNA modification, iron homeostasis, and DNA damage.

Main Results:

• Trmt61a loss in HSPCs led to reduced N1-methyladenosine (m¹A) levels and global translation efficiency decline.
• Trmt61a deficiency caused ribosomal stalling at specific codons in transferrin receptor (Tfrc) mRNA, impairing Tfrc synthesis.
• Reduced Tfrc expression resulted in intracellular iron depletion, DNA damage, and compromised HSPC survival.

Conclusions:

• Identified a novel Trmt61a-m¹A-Tfrc pathway essential for HSPC maintenance.
• Demonstrated that tRNA modification is critical for iron homeostasis and preventing DNA damage in HSPCs.
• Provided mechanistic insights into hematopoietic disorders and potential therapeutic targets.