MIRA Title: Dynamics and evolution of synthetic and natural gene regulatory networks Tissues or microbial cell populations can consist of millions of cells, each of which contains billions of molecules. Central among these molecules, DNA stores information in protein-coding genes, but also in noncoding, gene-regulatory regions. Gene products binding to such regions form complex gene regulatory networks that influence the behavior of individual cells and thereby cell populations. Changes in DNA sequence can alter these networks, making cell populations better adapted in various environments, contributing to genetic evolution. Yet, to learn how gene networks control cell populations, we must understand how network dynamics and stochasticity affects cells and thereby cell populations. Answering these questions should help us understand the behavior and evolution of cell populations, which are the bases of cancer progression and microbial drug resistance. To attack this problem, we have developed computational models of natural regulatory networks to understand how they modulate nongenetic diversity in cell populations. We have also designed synthetic gene networks to control the variability of protein expression in yeast and mammalian cells. Now we plan to connect these research directions, using synthetic gene networks to generate specific gene expression patterns in space and time that serve as signals for natural gene networks, studying the subsequent effects on cell population behavior and evolution by computational modeling and experimental evolution. Overall, these studies will shed light on how complex networks enable control across scales of space and time in biology, from molecules to cells. Addressing these questions will teach us how to control evolving cell populations, which is relevant for understanding, predicting and possibly preventing cancer and microbial resistance.
MIRA Title: Dynamics and evolution of synthetic and natural gene regulatory networks Genes influence the behavior of cells, and cause normal human tissues to become cancerous, or drug-sensitive microbial populations to become drug-resistant. To cure diseases, we need to understand how genes control cells and cell populations ? but this is not simple because genes do not accomplish their tasks alone; rather, they regulate each other, forming complex gene regulatory networks that function in a stochastic manner. We propose to study how natural gene networks function and evolve by developing computational models that mimic their behavior, and by perturbing them with human-designed synthetic gene networks, hoping to understand their function from the consequent changes in cell population behavior and evolution.
| Charlebois, Daniel A; Diao, Junchen; Nevozhay, Dmitry et al. (2018) Negative Regulation Gene Circuits for Efflux Pump Control. Methods Mol Biol 1772:25-43 |
| Charlebois, Daniel A; Hauser, Kevin; Marshall, Sylvia et al. (2018) Multiscale effects of heating and cooling on genes and gene networks. Proc Natl Acad Sci U S A 115:E10797-E10806 |
| Shao, Qiuyan; Cortes, Michael G; Trinh, Jimmy T et al. (2018) Coupling of DNA Replication and Negative Feedback Controls Gene Expression for Cell-Fate Decisions. iScience 6:1-12 |
| Li, Chunhe; Balazsi, Gabor (2018) A landscape view on the interplay between EMT and cancer metastasis. NPJ Syst Biol Appl 4:34 |
| Cortes, Michael G; Trinh, Jimmy T; Zeng, Lanying et al. (2017) Late-Arriving Signals Contribute Less to Cell-Fate Decisions. Biophys J 113:2110-2120 |
| Bódi, Zoltán; Farkas, Zoltán; Nevozhay, Dmitry et al. (2017) Phenotypic heterogeneity promotes adaptive evolution. PLoS Biol 15:e2000644 |
| Firman, Taylor; Balázsi, Gábor; Ghosh, Kingshuk (2017) Building Predictive Models of Genetic Circuits Using the Principle of Maximum Caliber. Biophys J 113:2121-2130 |
