Rational Design of Synthetic Yeast Promoters Using Systems-Level Bioinformatics Models

Promoters are a key component in metabolic engineering and synthetic biology.  These elements enable expression of heterologous genes, provide regulation of genetic circuits, and establish the basis for wholly rewired cells capable of producing new biochemical products.  As such, a large amount of effort has been expended to characterize and synthesize both endogenous and synthetic promoters.  Traditionally, new promoters have been generated through random mutagenesis of native promoters, bioprospecting to find non-native promoters, and synthetic hybrid promoters.  However, with the exception of the latter example, little progress has been made to rationally and systematically engineer promoters for a prescribed activity level.  In this presentation, we describe a new approach—namely a model-driven promoter design tool.  Specifically, we highlight recent progress in using models to rationally re-design endogenous yeast promoters.  In each of these cases, the rationally designed promoters followed the expected transcriptional output.   This work therefore represents a fundamentally new method for understanding promoter architecture with regards to expression level.  Moreover, this work enables rational design of synthetic parts.