430845 Genome-Scale Modeling of the Core Proteome of Metabolism and Expression, and Its Transcriptional Regulation

Monday, November 9, 2015: 3:15 PM
155A (Salt Palace Convention Center)
Laurence Yang, Bioengineering, University of California, San Diego, La Jolla, CA and Bernhard O. Palsson, Department of Bioengineering, University of California, San Diego, La Jolla, CA

The cell ‘chassis’ is of fundamental importance for synthetic biology applications. To predictively engineer this chassis, a systems biology understanding of it is critical. In this work, we broaden our understanding of the chassis using integrated genome-scale models of metabolism and expression. We first define a core proteome consisting of 356 gene products, accounting for 44% of the Escherichia coli proteome by mass based on proteomics data. This core proteome includes 212 genes not found in previous comparative genomics-based core proteome definitions, accounts for 65% of known essential genes in E. coli, and has functional overlap with minimal genomes (Buchnera aphidicola and Mycoplasma genitalium) (AUC = 0.78). Based on transcriptomics data across growth conditions and genetic backgrounds, the systems biology core proteome is significantly enriched in non-differentially expressed genes, and depleted in differentially expressed genes. Compared to the non-core, core gene expression levels are also similar across genetic backgrounds. Furthermore, core genes exhibit significantly more complex transcriptional and post-transcriptional regulatory features (40% more transcription start sites per gene, >20% longer 5’UTR). Thus, genome-scale systems biology approaches rigorously identify a functional core proteome needed to support growth. This framework, discerned and validated using high-throughput datasets, facilitates a mechanistic understanding of systems-level core proteome function through in silico models. We then investigate how the core proteome is regulated using a genome-scale, transcriptional regulatory network of E. coli. Taken together, the tightly regulated core proteome of E. coli comprises a fundamental repertoire of genes and biological functions that are of importance to a broad range of microbial synthetic biology applications.

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