Hysteresis in a synthetic mammalian gene network

Abstract

Bistable and hysteretic switches, enabling cells to adopt multiple internal expression states in response to a single external input signal, have a pivotal impact on biological systems, ranging from cell-fate decisions to cell-cycle control. We have designed a synthetic hysteretic mammalian transcription network. A positive feedback loop, consisting of a transgene and transactivator (TA) cotranscribed by TA's cognate promoter, is repressed by constitutive expression of a macrolide-dependent transcriptional silencer, whose activity is modulated by the macrolide antibiotic erythromycin. The antibiotic concentration, at which a quasi-discontinuous switch of transgene expression occurs, depends on the history of the synthetic transcription circuitry. If the network components are imbalanced, a graded rather than a quasi-discontinuous signal integration takes place. These findings are consistent with a mathematical model. Synthetic gene networks, which are able to emulate natural gene expression behavior, may foster progress in future gene therapy and tissue engineering initiatives.synthetic biology ͉ synthetic gene networks ͉ bistability ͉ erythromycin ͉ feedback-loop

A synthetic mammalian gene circuit reveals antituberculosis compounds

“…Synthetic gene circuits have dramatically increased progress on gene-function relationships in the postgenomic era (8)(9)(10)(11)(21)(22)(23)(24)(25). They also continue to provide the key parts for synthetic biologists to decipher natural gene network dynamics (8)(9)(10) and to reprogram cellular function for production of important precursor drugs (23).…”

“…They also continue to provide the key parts for synthetic biologists to decipher natural gene network dynamics (8)(9)(10) and to reprogram cellular function for production of important precursor drugs (23). We have engineered a synthetic gene network in human cells for screening of functional antimicrobial agents with precise target specificity, undetectable cytotoxicity, and the capacity to reach the cytosol to eliminate intracellular pathogens.…”

Mammalian synthetic biology: emerging medical applications

“…Moreover, similarly to electronic circuits, several multicomponent circuits with complex trigger-controlled topology have been designed with time-delay [116], bandpass [117] and hysteretic [118] properties. A gene network operated by a Boolean AND gate was applied for targeting cancer cells [119], where the AND gate activity was achieved when both pre-set conditions were met, leading to the expression of apoptotic genes and cancer cell death.…”

Application of Synthetic Biology to Regenerative Medicine

“…They can be layered to yield more intricate functions, even though it remains difficult to predict the behaviour of complex combinations. Introducing feedback loops in such circuits allows the design of systems showing hysteretic signal integration [35] or bimodal switch characteristics [36]. Rinaudo et al [37] have engineered a 'universal' RNAi-based Boolean logic evaluator in which the molecular endogenous inputs are encoded by small interfering RNAs (siRNAs).…”