A tunable synthetic mammalian oscillator

abstract

Autonomous and self-sustained oscillator circuits mediating the periodic induction of specific target genes are minimal genetic time-keeping devices found in the central and peripheral circadian clocks1, 2. They have attracted significant attention because of their intriguing dynamics and their importance in controlling critical repair3, metabolic4 and signalling pathways5. The precise molecular mechanism and expression dynamics of this mammalian circadian clock are still not fully understood. Here we describe a synthetic mammalian oscillator based on an auto-regulated sense–antisense transcription control circuit encoding a positive and a time-delayed negative feedback loop, enabling autonomous, self-sustained and tunable oscillatory gene expression. After detailed systems design with experimental analyses and mathematical modelling, we monitored oscillating concentrations of green fluorescent protein with tunable frequency and amplitude by time-lapse microscopy in real time in individual Chinese hamster ovary cells. The synthetic mammalian clock may provide an insight into the dynamics of natural periodic processes and foster advances in the design of prosthetic networks in future gene and cell therapies.

top 10 topics

{ positive noise feedback construction negative synthetic circuits intrinsic fluctuations naturally }
{ gene genes expression tissues regulation coexpression tissuespecific expressed tissue regulatory }
{ contrast resolution imaging conventional molecules resonance living magnetic localization determination }
{ genome genomic mammalian bias recombination mouse chromosome ratio substitutions substitution }
{ dynamics modeling simulation simulations unified membrane modeled diagrams fusion configuration }
{ cells cell cancer signaling differentiation stem tumor breast proliferation cancers }
{ cellular metabolic growth coli chemical biochemical reactions reconstruction escherichia metabolism }
{ events temporal frequency place position locations encoding ensemble cycle oscillations }
{ communication technologies attention dimensions explores aspect received messages daily channels }
{ mechanism synaptic synthesis gain longterm strength plasticity induced induction mediated }

top 10 topics after corrections

{ positive noise feedback construction negative synthetic circuits intrinsic fluctuations naturally }
{ genetic disease association quantitative diseases traits associations loci phenotypic phenotypes }
{ cellular metabolic growth coli chemical biochemical reactions reconstruction escherichia metabolism }
{ interaction largescale yeast cerevisiae saccharomyces mass proteomics proteome highthroughput hubs }
{ gene genes expression tissues regulation coexpression tissuespecific expressed tissue regulatory }
{ contrast resolution imaging conventional molecules resonance living magnetic localization determination }
{ based world real characteristics actual exploring exploration quite navigation possibilities }
{ genome genomic mammalian bias recombination mouse chromosome ratio substitutions substitution }
{ analysis analyses analyzing exploratory displaying analysts import investigators lesser analyze }
{ events temporal frequency place position locations encoding ensemble cycle oscillations }

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