Flux analysis reveals specific regulatory modalities of gene expression

Abstract

The level of a given protein is determined by rates of mRNA and protein synthesis and degradation. The reliable quantification of these rates is thus essential to understand how protein levels are regulated. While several studies have quantified the contribution of different steps of gene expression in regulating protein levels, these are limited by the use of equilibrium approximations when studying out-of-equilibrium biological systems. Here we introduce flux analysis to quantify the contribution of gene expression steps to regulate the dynamics of the expression level for specific proteins. We use flux analysis to analyze a published RNA-seq and proteomics dataset of mouse bone marrow-derived DCs stimulated with LPS. Our analysis revealed six regulatory modalities shared by sets of genes with clear functional signatures. We also find that protein degradation plays a stronger role than expected in the adaptation of protein levels to LPS stimulation. These findings suggest that shared regulatory strategies can lead to versatile responses at the protein level and highlight the importance of going beyond steady-state approximations to uncover the dynamic contribution of different steps of gene expression to protein levels.