A snoRNA-tRNA modification network governs codon-biased cellular states.

Area of Science:

• Molecular Biology
• RNA Biology
• Cellular Metabolism

Background:

• The balance between tRNA supply and codon demand is crucial for cellular translation.
• The precise regulatory mechanisms and functional outcomes of this balance are not fully understood.
• Small nucleolar RNAs (snoRNAs) are known to modify ribosomal RNA, but their roles in tRNA modification are less clear.

Purpose of the Study:

• To elucidate the targets and functions of snoRNAs in cellular translation.
• To investigate the role of snoRNAs in tRNA modification and its impact on cellular states.
• To resolve the mystery of orphan snoRNAs and their contribution to the translation economy.

Main Methods:

• PARIS2 interactome capture
• Structure modeling
• Conservation analysis
• RNA-protein interaction analysis
• Modification mapping
• CRISPR-Cas9 gene editing (knockout/knockdown) in HEK293 cells and mouse embryonic stem cells

Main Results:

• Identified a network of snoRNA-tRNA interactions essential for global tRNA modifications, including 2'-O-methylation.
• Demonstrated that loss of snoRNAs D97/D133 leads to reduced target tRNA levels and codon adaptation.
• Showed that D97/D133 knockout suppresses proliferation-related gene programs and promotes development-related programs in human and mouse cells.

Conclusions:

• snoRNAs play a critical role in regulating tRNA modifications and cellular fate.
• The D97/D133 snoRNAs are key regulators of methionine tRNA modification, influencing the balance between proliferation and development.
• This work uncovers a novel function for snoRNAs in controlling codon-biased cellular states.