18 October 2017

What transcriptional noise tells us about the cell inside

Speaker: Victor de Lorenzo

Venue: Central Lecture Theatre (CLT), at 3:30 pm on Friday, 3rd November 2017

Systems Biology Program. Centro Nacional de Biotecnologia, CSIC, C/ Darwin, 3 (Campus de Cantoblanco), Madrid 28049, Spain.

Abstract

Transcriptional noise is a necessary consequence of the molecular events that drive gene expression in prokaryotes. However, the m-xylene degrading soil bacterium Pseudomonas putida mt-2 seem to have co-opted evolutionarily such a noise for deploying a metabolic diversification strategy that allows a cautious exploration of new chemical landscapes. In reality, noise is not only the mere consequence of stochasticity, but also a signal that reflects the upstream physical dynamics of the cognate molecular machinery. Noise of catabolic promoters can thus be exploited to deploy beneficial phenotypes such as metabolic bet-hedging and/or division of biochemical labour. Although the role of upstream promoter-regulator interplay in the origin of this noise is little understood, its specifications are probably ciphered in flow cytometry data patterns. We studied the activity of the Pm promoter of Pseudomonas putida mt-2 and its cognate regulator XylS by following expression of Pm-gfp fusions in single cells. Using mathematical modelling and computational simulations, we determined the kinetic properties of the system and used them as a baseline code to interpret promoter activity in terms of upstream regulator variability. Transcriptional noise was predicted to depend on the intracellular physical distance between regulator source (where XylS is produced) and the target promoter. Experiments with engineered bacteria in which this distance is minimised or enlarged confirmed the predicted effects of source/target proximity on noise patterns. This approach allowed deconvolution of cytometry data into mechanistic information on gene expression flow. It also provided a basis for selecting programmable noise levels in synthetic regulatory circuits.

Goñi-Moreno Á, Benedetti I, Kim J, de Lorenzo V. (2017) Deconvolution of Gene Expression Noise into Spatial Dynamics of Transcription Factor-Promoter Interplay. ACS Synth Biol. 6: 1359-1369

Guantes R, Benedetti I, Silva-Rocha R, de Lorenzo V. (2016) Transcription factor levels enable metabolic diversification of single cells of environmental bacteria. ISME J. 10: 1122-1133

Silva-Rocha, R. and de Lorenzo, V. (2012) Stochasticity of TOL plasmid catabolic promoters sets a bimodal expression regime in Pseudomonas putida mt-2 exposed to m-xylene. Mol. Microbiol. 86: 199- 211