Coordinated transcriptional and translational resource allocation shapes gene expression

Abstract

The coordinated interplay of transcription and translation govern the overall rate of protein synthesis. Although this coordination of transcription and translation has been widely studied in different contexts, how it shapes cellular resource utilization and global transcriptional–translational resource allocation remains unclear. To address this, we reformulate the conventional Totally Asymmetric Simple Exclusion Process (TASEP) α − β phase diagram into a biologically relevant α − ω representation, where initiation (α) and elongation (ω) rates reflect investment in molecular machinery and substrate-dependent translocation, while β represents the termination rate. In this α − ω representation, the conventional low-density (LD), high-density (HD), and maximal-current (MC) classifications no longer characterize these TASEP regimes and are instead more naturally interpreted as initiation-limited (IL), termination-limited (TL), and elongation-limited (EL) regimes, respectively. Then, mapping E. coli genes onto this phase space reveals that they predominantly occupy the initiation-limited (IL) regime, where ribosome utilization efficiency is optimized despite lower protein synthesis flux, suggesting cells prioritize efficient resource utilization over maximal protein production capacity. We further show that transcriptional and translational resource-utilization efficiencies are intrinsically coupled, such that improving resource utilization in one process may increase the biosynthetic burden on the other. Consequently, local optimization of transcriptional or translational throughput alone does not necessarily maximize the global efficiency of protein production, which instead emerges from coordinated tuning of both processes. Then, using constrained optimization with Lagrangian multipliers, we identify optimal transcriptional and translational resource-allocation strategies that minimize biosynthetic cost and define an upper bound on achievable resource-utilization efficiency. This analysis reveals how coordinated tuning of transcriptional and translational initiation rates can enable efficient cellular resource allocation. Together, these findings suggest efficient gene expression is governed by global resource-allocation constraints arising from molecular traffic during transcription and translation.