Decoding Codon Bias: The Role of tRNA Modifications in Tissue-Specific Translation

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• The tRNA epitranscriptome plays a crucial role in regulating mRNA translation.
• Understanding tissue-specific tRNA expression and modifications is vital for deciphering codon decoding.
• Current knowledge on the tRNA epitranscriptome's role in fine-tuning translation at the tissue level is incomplete.

Purpose of the Study:

• To analyze tRNA expression, modifications, and codon optimality across seven mouse tissues.
• To investigate the tissue-specific enrichment patterns of tRNA modifications.
• To explore the potential of tRNA modification knowledge for optimizing gene and mRNA therapeutics.

Main Methods:

• Analysis of tRNA expression and modifications in seven mouse tissues.
• Assessment of codon optimality.
• In vivo synthesis and delivery of codon-mutated EGFP (Enhanced Green Fluorescent Protein) to test the impact of Queuosine (Q) codon mutations.

Main Results:

• Distinct tissue-specific patterns of tRNA modifications were observed.
• Queuosine (Q) tRNA modification was most enriched in the brain.
• Mitochondrial tRNA modifications and tRNA expression were highest in the heart.
• Mutant EGFP protein levels were downregulated in the liver (low Q) but unchanged in the brain (high Q).

Conclusions:

• Tissue-specific tRNA modification enrichments are essential for understanding codon decoding and bias.
• Knowledge of tRNA modifications can be leveraged to develop tissue- or cell-specific gene and mRNA therapeutics.
• This study provides a foundation for engineering targeted gene therapies based on epitranscriptomic profiles.