DeVore Michelle L, Bazzini Ariel A
Stowers Institute for Medical Research, 1000 E 50th Street, Kansas City, MO 64110, USA.
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA.
G3 (Bethesda). 2024 Oct 24;14(12). doi: 10.1093/g3journal/jkae247.
The ribosome plays a crucial role in translating mRNA into protein; however, the genetic code extends beyond merely specifying amino acids. Upon translation, codons, the three-nucleotide sequences interpreted by ribosomes, have regulatory properties affecting mRNA stability, a phenomenon known as codon optimality. Codon optimality has been previously observed in vertebrates during embryogenesis, where specific codons can influence the stability and degradation rates of mRNA transcripts. In our previous work, we demonstrated that codon optimality impacts mRNA stability in human cell lines. However, the extent to which codon content influences vertebrate gene expression in vivo remained unclear. In this study, we expand on our previous findings by demonstrating that codon optimality has a robust effect on homeostatic mRNA and protein levels in whole zebrafish during normal physiological conditions. Using reporters with nearly identical nucleotide sequences but different codon compositions, all expressed from the same genomic locus, we show that codon composition can significantly influence gene expression. This study provides new insights into the regulatory roles of codon usage in vertebrate gene expression and underscores the importance of considering codon optimality in genetic and translational research. These findings have broad implications for understanding the complexities of gene regulation and could inform the design of synthetic genes and therapeutic strategies targeting mRNA stability.
核糖体在将信使核糖核酸（mRNA）翻译成蛋白质的过程中起着至关重要的作用；然而，遗传密码的作用不仅仅局限于指定氨基酸。在翻译过程中，密码子（即核糖体解读的三核苷酸序列）具有影响mRNA稳定性的调控特性，这一现象被称为密码子最优性。此前在脊椎动物胚胎发育过程中已观察到密码子最优性，其中特定密码子可影响mRNA转录本的稳定性和降解速率。在我们之前的工作中，我们证明了密码子最优性会影响人类细胞系中的mRNA稳定性。然而，密码子组成在体内对脊椎动物基因表达的影响程度仍不清楚。在这项研究中，我们通过证明在正常生理条件下，密码子最优性对整个斑马鱼体内稳态mRNA和蛋白质水平具有强大影响，扩展了我们之前的研究结果。使用具有几乎相同核苷酸序列但密码子组成不同的报告基因，所有这些报告基因均从同一基因组位点表达，我们表明密码子组成可显著影响基因表达。这项研究为密码子使用在脊椎动物基因表达中的调控作用提供了新的见解，并强调了在遗传和翻译研究中考虑密码子最优性的重要性。这些发现对于理解基因调控的复杂性具有广泛影响，并可为合成基因的设计以及针对mRNA稳定性的治疗策略提供参考。
