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

Codon usage biases play a significant role in determining gene expression levels. Codon usage was thought to primarily influence translation-dependent processes. Using an unbiased genome-wide screening to search for factors involved in codon usage effects on gene expression, we identified the CCR4-NOT complex subunit CNOT4 and many nuclear factors, including nuclear RNA exosome, PAXT complex components, and transcription factors. The CCR4-NOT complex has been shown to affect codon usage-dependent co-translational mRNA decay in yeast. Surprisingly, human CNOT4 was found to influence codon usage-dependent gene expression largely by its impact on nuclear RNA levels due to transcriptional effect. On the other hand, nuclear exosome and PAXT complex, regulate nuclear mRNA stability through the RNA quality control pathway, leading to preferential cytoplasmic accumulation of mRNAs with optimal codon usage. Overall, our results show that different nuclear mechanisms play a key role in determining nucleotide composition-dependent gene expression levels in human cells.