Exploiting fluctuations in gene expression to detect causal interactions between genes

Characterizing and manipulating cellular behavior requires a mechanistic understanding of the causal interactions between cellular components. We present an approach to detect causal interactions between genes without the need to perturb the physiological state of cells. This approach exploits naturally occurring cell-to-cell variability which is experimentally accessible from static population snapshots of genetically identical cells without the need to follow cells over time. Our main contribution is a simple mathematical relation that constrains the propagation of gene expression noise through biochemical reaction networks. This relation allows us to rigorously interpret fluctuation data even when only a small part of a complex gene regulatory process can be observed. We show how this relation can, in theory, be exploited to detect causal interactions by synthetically engineering a passive reporter of gene expression, akin to the established 'dual reporter assay'. While the focus of our contribution is theoretical, we also present an experimental proof-of-principle to demonstrate the real-world applicability of our approach in certain circumstances. Our experimental data suggest that the method can detect causal interactions in specific synthetic gene regulatory circuits in Escherichia coli, confirming our theoretical result in a narrow set of controlled experimental settings. Further work is needed to show that the approach is practical on a large scale, with naturally occurring gene regulatory networks, or in organisms other than E. coli.