Biomics

A discrete-continuous model of a molecular genetic system for controlling the differential activity of genes in cells of a clonal population of bacteria has been constructed. The system consists of a 3-operon oscillator and a pair of 2-operon triggers interconnected by transcriptional repressors. The model takes into account the main kinetic parameters of gene expression: gene product synthesis and degradation rates, threshold concentrations of transcription factors, and time delays. The system has one periodic mode (with an active oscillator) and two equilibrium states (with an inactivated oscillator). The possibility of coexistence of modes is determined by the ratios of the gene products synthesis and degradation rates of all three dynamic modules of the system. Computer experiments were carried out under conditions simulating the exponential growth of the cell population, taking into account the linear growth of the individual cell volume in the cell cycle. It was shown that in a wide range of the kinetic parameter values, each mode can be stably inherited in a number of cell divisions. This property refers the gene network to the class of epigenes – special hereditary units in which part of the hereditary information is stored, encoded and transmitted to progeny beyond the primary structure of genomic DNA molecules. The model revealed a typical ratio of network gene expression rates at which a growing cell population splits, initially epigenetically homogeneous (the initial state is the periodic mode), into three subpopulations that differ in the epigenetic status of the cells that form them (alternative patterns are the periodic mode and two equilibrium states). Corresponding cell epigenotypes can differ in null, low or high expression of the target genes and, thus, determine the adaptive strategies for both natural and epigenetically modified bacteria.

control system, trigger, oscillator, molecular dynamics

1. Elowitz M.B., Leibler S.A. A synthetic oscillatory network of transcriptional regulators. Nature. 2000. V. 403. P. 335-338. doi: 10.1038/35002125

2. Esquerré T., Laguerre S., Turlan C., Carpousis A.J., Girbal L., Cocaign-Bousquet M. Dual role of transcription and transcript stability in the regulation of gene expression in Escherichia coli cells cultured on glucose at different growth rates. Nucleic Acids Res. 2014. V. 42(4). P. 2460–2472. doi: 10.1093/nar/gkt1150

3. Galimzyanov A.V. «GREENCE» Technology for In Silico Analysis of Gene Network Dynamics in Individual Cells of a Clonal Population. Biophysics (Biofizika). 2006. V. 51, Suppl. 1. P. S66-S69. doi: 10.1134/S0006350906070141

4. Galimzyanov A.V., Stupak E.E., Tchuraev R.N. Epigene networks: Theory, models, and experiment. Biol. Bull. Rev. 2019. V. 9. P. 484-490. doi: 10.1134/S2079086419060021

5. Klumpp S., Zhang Z., Hwa T. Growth rate-dependent global effects on gene expression in bacteria. Cell. 2009. V. 139(7). P. 1366-1375. doi: 10.1016/j.cell.2009.12.001

6. Li T., Dong Y., Zhang X., Ji X., Luo C., Lou C. Zhang H.M., Ouyang Q. Engineering of a genetic circuit with regulatable multistability. Integr Biol (Camb). 2018. V. 10(8). P. 474-482. doi: 10.1039/c8ib00030a

7. Sánchez-Romero M.A., Casadesús J. The bacterial epigenome. Nat. Rev. Microbiol. 2020. V. 18. P. 7-20. doi: 10.1038/s41579-019-0286-2

8. Tchuraev R.N., Galimzyanov A.V. Gene and epigene networks: Two levels in organizing the hereditary system. J. Theor. Biol. 2009. V. 259. P. 659-669. doi: 10.1016/j.jtbi.2009.03.034

9. Tchuraev R.N., Stupak E.E., Stupak I.V., Galimzyanov A.V. A new epigene property: Metastable epigenotypes. Dokl. Biol. Sci. 2006. V. 406. P. 97-99. doi: 10.1134/S0012496606010285

10. Tchuraev R.N., Stupak I.V., Tropynina T.S., Stupak E.E. Epigenes: design and construction of new hereditary units. FEBS Lett. 2000. V. 486. P. 200–202. doi: 10.1016/S0014-5793(00)02300-0