The Roles of Codon Usage in Translational and Transcriptional Regulation on Gene Expression

Codon usage bias refers to the universal feature of genome that synonymous codons are used at different frequency. Codon usage plays critical roles in determining gene expression levels through impacting multiple fundamental cellular processes. Although the correlation between codon usage and gene expression level has long been observed, the underlying mechanisms are still largely unclear. In the first part, I demonstrate the mechanism of codon usage determining translation efficiency. The slow decoding rate of nonoptimal codon causes ribosome stalling on mRNA, which leads to premature termination of translation and reduced protein production. This process is conserved from Neurospora to Drosophila. In addition, I demonstrate that the premature termination of translation is mediated by the canonical release factor eRF1, which recognizes ribosomes stalled at nonoptimal codons. Together, I propose a model that explains the impact of codon usage on translation efficiency. In the second part, I investigate the role of promoter in codon- dependent gene expression at transcription level. I show that codon usage and sequence downstream of core promoter act in concert to determine the transcription level. Moreover, I identify the regulatory element in Hsp70 promoter that upregulates the transcription of genes containing nonoptimal codons. The differential transcriptional level is achieved through epigenetic regulations affecting nucleosome density and H3K27ac level and premature termination pathway mediated by Ars2, NEXT complex and nuclear exosome. Collectively, these results show that codon usage and promoter impact transcription through multilayer regulatory mechanisms.