Zhou Zhipeng, Dang Yunkun, Zhou Mian, Li Lin, Yu Chien-Hung, Fu Jingjing, Chen She, Liu Yi
Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390.
Department of Physiology, The University of Texas Southwestern Medical Center, Dallas, TX 75390; State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China.
Proc Natl Acad Sci U S A. 2016 Oct 11;113(41):E6117-E6125. doi: 10.1073/pnas.1606724113. Epub 2016 Sep 26.
Codon usage biases are found in all eukaryotic and prokaryotic genomes, and preferred codons are more frequently used in highly expressed genes. The effects of codon usage on gene expression were previously thought to be mainly mediated by its impacts on translation. Here, we show that codon usage strongly correlates with both protein and mRNA levels genome-wide in the filamentous fungus Neurospora Gene codon optimization also results in strong up-regulation of protein and RNA levels, suggesting that codon usage is an important determinant of gene expression. Surprisingly, we found that the impact of codon usage on gene expression results mainly from effects on transcription and is largely independent of mRNA translation and mRNA stability. Furthermore, we show that histone H3 lysine 9 trimethylation is one of the mechanisms responsible for the codon usage-mediated transcriptional silencing of some genes with nonoptimal codons. Together, these results uncovered an unexpected important role of codon usage in ORF sequences in determining transcription levels and suggest that codon biases are an adaptation of protein coding sequences to both transcription and translation machineries. Therefore, synonymous codons not only specify protein sequences and translation dynamics, but also help determine gene expression levels.
密码子使用偏好存在于所有真核生物和原核生物基因组中，在高表达基因中，最优密码子的使用频率更高。此前认为密码子使用对基因表达的影响主要是通过其对翻译的作用来介导的。在此，我们表明在丝状真菌粗糙脉孢菌中，全基因组范围内密码子使用与蛋白质水平和mRNA水平都密切相关。基因密码子优化也会导致蛋白质和RNA水平的强烈上调，这表明密码子使用是基因表达的一个重要决定因素。令人惊讶的是，我们发现密码子使用对基因表达的影响主要源于对转录的作用，并且在很大程度上独立于mRNA翻译和mRNA稳定性。此外，我们表明组蛋白H3赖氨酸9三甲基化是一些具有非最优密码子的基因密码子使用介导的转录沉默的机制之一。这些结果共同揭示了密码子使用在开放阅读框序列中决定转录水平方面出人意料的重要作用，并表明密码子偏好是蛋白质编码序列对转录和翻译机制的一种适应。因此，同义密码子不仅决定蛋白质序列和翻译动态，还有助于确定基因表达水平。
