E. coli gene regulatory networks are inconsistent with gene expression data.

Gene regulatory networks (GRNs) and gene expression data form a core element of systems biology-based phenotyping. Changes in the expression of transcription factors are commonly believed to have a causal effect on the expression of their targets. Here we evaluated in the best researched model organism, Escherichia coli, the consistency between a GRN and a large gene expression compendium. Surprisingly, a modest correlation was observed between the expression of transcription factors and their targets and, most noteworthy, both activating and repressing interactions were associated with positive correlation. When evaluated using a sign consistency model we found the regulatory network was not more consistent with measured expression than random network models. We conclude that, at least in E. coli, one cannot expect a causal relationship between the expression of transcription and factors their targets, and that the current static GRN does not adequately explain transcriptional regulation. The implications of this are profound as they question what we consider established knowledge of the systemic biology of cells and point to methodological limitations with respect to single omics analysis, static networks and temporality.