Dynamic mechanism of phase variation in bacteria based on multistable gene regulatory networks

Abstract

Phase variation, which causes splitting the homogeneous bacterial population into subpopulations of the cells with different and reversible activity of the same variable genes, provide bacteria with wide opportunities to implement their adaptation strategies. Meanwhile, the gene networks perform integral regulation of the genome and control over the formation of phenotypic traits of the organism. Mechanisms of phase variation, such as genomic rearrangements and DNA methylation, affect the regulatory contours of gene networks. At the same time, the gene networks themselves may be the key cause of the appearance of phenotypic variants. Here we propose a new class of gene networks that represent a ring connection of genetic triggers based on an oscillator with cyclic gene repression, termed the tringers. It is shown in silico that the tringers are able to provide splitting the homogeneous bacterial population into cellular subpopulations with alternative expression of controlled genes (phases), stable inheritance of phases, and switching between them, in particular, returning to a homogeneous state. Switching can be carried out under the influence of external and internal factors, both directly and by signals from specialized molecular genetic systems of the cell, in particular, the response to various types of stress. Such epigenetic structures with the function of a phase switching controller are possible in nature and applicable in synthetic biology.