Abstract

A global transcriptional regulatory network was generated in the pathogenic bacterium Enterococcus faecalis in order to understand how this organism can activate and coordinate its expression at different copper concentrations. The topological evaluation of the network showed common patterns described in other organisms. Integrating microarray experiments allowed the identification of two sub-networks activated at low (0.05 mM CuSO4) and high (0.5 mM CuSO4) concentrations of copper. The analysis indicates the presence of specific functionally activated modules induced by copper levels, highlighting the regulons LysR and ArgR as global regulators and CopY, Fur and LexA as local regulators. Taking advantage of the fact that E. faecalis presented a homeostatic module, we produced an in vivo intervention by removing this system from the cell without affecting the connectivity of the global transcriptional network. This strategy led us to find that this bacterium can reconfigure its gene expression to maintain cellular homeostasis, activating new modules principally related to glucose metabolism and transcriptional processes. Finally, these results position E. faecalis as the most complete and controllable systemic model organism for copper homeostasis available to date.