Abstract
Introns are key regulators of eukaryotic gene expression and present a potentially powerful tool for the design of synthetic eukaryotic gene expression systems. However, intronic control over gene expression is governed by a multitude of complex, incompletely understood, regulatory mechanisms. Despite this lack of detailed mechanistic understanding, here we show how a relatively simple model enables accurate and predictable tuning of synthetic gene expression system in yeast using several predictive intron features such as transcript folding and sequence motifs. Using only natural Saccharomyces cerevisiae introns as regulators, we demonstrate fine and accurate control over gene expression spanning a 100 fold expression range. These results broaden the engineering toolbox of synthetic gene expression systems and provide a framework in which precise and robust tuning of gene expression is accomplished.
Highlights
Advancements and innovations in synthetic and computational biology have revolutionized our ability to rationally engineer libraries of single synthetic genetic elements and have increased our capacity to finely tune the expression of genes according to specification
We show that Introns, pivotal regulators of Eukaryotic gene expression, can be rationally engineered to control a synthetic gene expression system of a Eukaryote
We developed a unique reporter-based system to evaluate the effects of engineering splicing in synthetic biology and show that the entire intron repertoire of S. cerevisiae can be accurately used to rationally engineer gene expression
Summary
Advancements and innovations in synthetic and computational biology have revolutionized our ability to rationally engineer libraries of single synthetic genetic elements (such as promoters or ribosome binding sites) and have increased our capacity to finely tune the expression of genes according to specification. Establishing reliable rules for applying regulatory genetic elements in the engineering of synthetic gene expression systems is still a major challenge in synthetic biology. Since splicing of introns must be performed before translation can begin, it is a key step in controlling gene expression. In this study we broaden the repertoire of genetic elements for bio-engineering by showing how introns can be used to regulate gene expression in a synthetic gene
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