Nuclear effects play an important role in determining codon usage-dependent human gene expression.

Area of Science:

• Molecular Biology
• Gene Regulation
• RNA Biology

Background:

• Codon usage bias significantly impacts gene expression levels.
• Previously, codon usage effects were primarily linked to translation-dependent processes.

Purpose of the Study:

• To identify factors mediating codon usage effects on gene expression genome-wide.
• To investigate the role of the CCR4-NOT complex and nuclear factors in codon usage-dependent gene expression.

Main Methods:

• Unbiased genome-wide screening to identify relevant factors.
• Analysis of the CCR4-NOT complex subunit CNOT4 and nuclear factors like the RNA exosome and PAXT complex.

Main Results:

• CNOT4 influences codon usage-dependent gene expression via transcriptional effects on nuclear RNA levels.
• Nuclear exosome and PAXT complex regulate nuclear mRNA stability through RNA quality control.
• These mechanisms promote cytoplasmic accumulation of mRNAs with optimal codon usage.

Conclusions:

• Nuclear mechanisms, distinct from co-translational decay, are crucial for codon usage-dependent gene expression in human cells.
• Both transcriptional regulation by CNOT4 and mRNA stability control by nuclear exosome/PAXT complex are key players.