Global regulators facilitate adaptation to a phenotypic trade-off

Abstract

The fitness of organisms depends critically on regulatory strategies that balance multiple phenotypes, including physiological, developmental, and pathogenic. An important example is the trade-off between motility and growth determine competition for habitat colonization by microorganisms and the invasiveness of metastatic cells in cancer. Phenotype regulation relies on hierarchical gene networks, but how gene hierarchy contributes to adaptation remains unclear. Here, we show that global upstream regulators allow cells to adjust the impact of downstream local regulators in the context of a phenotypic trade-off. We performed single and double knockdowns of transcription factors in Escherichia Coli and measured their impact on swimming and growth in different environments. We observed that perturbations of local regulators affect only a specific phenotype independently of the genetic background, whereas perturbations of global regulators affect either one or both phenotypes to varying degrees depending on the genetic background. Global and local regulators strongly interact giving rise to sign, reciprocal sign and masking epistasis. Epistasis between particular genes is modulated by the environment, but only a restricted number of epistatic patterns are observed across environments. These epistatic constraints suggests that that local regulators should be typically acquired before tuning of the phenotypic trade-off by global regulators. These findings highlight the importance of pleiotropic regulators for coordinating phenotypic responses to complex environments and providing flexibility during evolution.