Hysteretic Genetic Circuit for Detection of Proteasomal
Degradation in Mammalian Cells
Posted on 2019-08-27 - 18:38
Synthetic
hysteretic mammalian gene circuits generating sustained
cellular responses to transient perturbations provide important tools
to investigate complex cellular behaviors and reprogram cells for
a variety of applications, ranging from protein production to cell
fate decisions. The design rules of synthetic gene circuits with controlled
hysteretic behaviors, however, remain uncharacterized. To identify
the criteria for achieving predictable control of hysteresis, we built
a genetic circuit for detection of proteasomal degradation (Hys-Deg).
The Hys-Deg circuit is based on a tetracycline-controlled transactivator
(tTA) variant engineered to interface with the ubiquitin proteasome
system (UPS). The tTA variant activates its own expression, generating
a positive feedback loop that is triggered by expression of another
tTA gene that is constitutively regulated. Guided by predictive modeling,
we characterized the hysteretic response of the Hys-Deg circuit. We
demonstrated that control of the hysteretic response is achieved by
modulating the ratio of expression of constitutive to inducible tTA.
We also showed that the system can be finely tuned through dosage
of the inducer tetracycline to calibrate the circuit for detection
of the desired levels of UPS activation. This study establishes the
design rules for building a hysteretic genetic circuit with an autoregulatory
feedback loop and provides a synthetic memory module that could be
easily integrated into regulatory gene networks to study and engineer
complex cellular behaviors.
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Zeng, Yimeng; Bhagyashree, Bachhav; Zhao, Wenting; Nguyen, Tram; Segatori, Laura (2019). Hysteretic Genetic Circuit for Detection of Proteasomal
Degradation in Mammalian Cells. ACS Publications. Collection. https://doi.org/10.1021/acssynbio.9b00074
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AUTHORS (5)
YZ
Yimeng Zeng
BB
Bachhav Bhagyashree
WZ
Wenting Zhao
TN
Tram Nguyen
LS
Laura Segatori