МОДЕЛИРОВАНИЕ СИСТЕМЫ ЭПИГЕНЕТИЧЕСКОЙ ПАМЯТИ С ТРАНСКРИПЦИОННОЙ РЕПРЕССИЕЙ И МЕТИЛИРОВАНИЕМ ДНК

Abstract

The in silico model of the epigenetic memory system synthesized in Escherichia coli [Maier et al., 2017, Nat. Comm., 8:15336] was developed. The system includes an artificial memory operon with DNA methyltransferase CcrM from Caulobacter crescentus methylating the promoter of this operon, and an engineered transcriptional repressor gene ZnF that blocks the same promoter in an unmethylated state. The memory operon, which is located on the maintenance plasmid, is controlled by a trigger plasmid carrying a specific arabinose-inducible operon. The artificial trigger operon functions as part of an expanded arabinose regulon. An additional model is used to describe the operation of the latter. The unified model of the memory control system takes into account positive and negative control by the regulatory protein araC, negative feedback self-regulation and negative direct, methylation-sensitive regulation by the ZnF protein, and DNA methylation. The models are built in the language of the formalism of the dynamic theory of molecular genetic control systems. The models were calculated in the SETIES software package to analyze the dynamics of control gene networks, dynamic epigenes and cell ensembles. Computer experiments have shown that the switch has two alternative functional modes, each of which is stable in a series of successive cell divisions. Both modes are characterized in terms of the molecular component dynamics of the artificial memory operon, the trigger operon, and the natural L-arabinose catabolism operon.