TIGP (BIO)—Codon Bias–Mediated Gene Regulation in animals: Temporal, Spatial, and Interventional Perspectives

Abstract

Codon usage bias is a universal feature across all domains of life.  We previously showed that codon bias regulates ribosomal translation speed, thereby influencing co-translational protein folding and ribosome stalling. In addition to its role in translational control, we also demonstrated that codon bias mediates transcriptional regulation through heterochromatin formation and modulation of polyadenylation. However, how codon bias influences gene expression and connects genotype to phenotype remains poorly understood, especially in higher eukaryotes. Here, I will present our recent findings suggesting that codon bias may be linked to learning and memory. Using Drosophila melanogaster as a model system, we found that optimization of the codons in the cAMP response element-binding protein (CREB) gene dampens olfactory learning, likely due to alterations in CREB protein structure. We further investigated the role of codon bias in mRNA translation across morphologically distinct human cell types and found that different cells preferentially use distinct sets of codons. Interestingly, such codon adaptation occurs not only among different cell types but also between subcellular compartments within the same cell. Finally, we sought to attenuate ribosomal translation speed in trans, mimicking the effect of slow codons to modulate co-translational protein folding. Using the cystic fibrosis transmembrane conductance regulator (CFTR) as a model, we found that CFTR folding and maturation can be fine-tuned through this approach.

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