Abstract
Synthetic biology is advancing into a new phase where real-world applications are emphasized. There is hence an urgent need for mathematical modeling that can quantitatively describe the behaviors of genetic devices in natural, fluctuating environments. We utilize an integrative circuit-host modeling framework to examine the dynamics of a genetic switch and its host cell in varying environments. For both steady-state and transient cases, we find increasing nutrient reduces the bistability region of the phase space and eventually drives the switch from bistability to monostability. In response, cellular growth and proteome partitioning experience the same transition. Antibiotic perturbations cause the similar circuit and host responses as nutrient variations. However, one difference is the trend of growth rate, which augments with nutrient but declines with antibiotic levels. The framework provides a mechanistic scheme to account for both the dynamic and static characteristics of the circuit-host system upon environmental perturbations, underscoring the intimacy of gene circuits and their hosts and elucidating the complexity of circuit behaviors arising from environmental variations.
Highlights
Research spanning two decades has demonstrated synthetic gene circuits as valuable tools for a wide variety of novel applications[1,2,3]
RNAs are binned based on their functions into three sectors, including mRNAs encoding proteins, tRNAs delivering amino acids to ribosomes, and ribosomal RNAs that are involved in ribosomes
After successful creation of a wide array of engineered gene circuits, synthetic biology is advancing into a new era wherein circuits are deployed in the real world
Summary
Research spanning two decades has demonstrated synthetic gene circuits as valuable tools for a wide variety of novel applications[1,2,3] They have been utilized for directing spatial patterns[4,5], regulating chemical biosynthesis[6], generating temporal dynamics[7,8,9] and establishing defined ecologies[10,11,12,13]. Integrative modeling, which fully acknowledges circuit-host interactions, has been proposed as a novel scheme to model gene circuit behaviors[22,23] This coarse-grained, dynamic modeling approach explicitly includes multi-layered interactions between circuits and their host caused by crosstalk and resource sharing. Our results elucidate complex environmental dependence of circuit behaviors and showcase the power of the integrative framework for understanding circuits under complex settings
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