Hysteresis in a synthetic mammalian gene network
Hysteresis in a synthetic mammalian gene network
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DOI：
10.1073/pnas.0500345102
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发表时间：
2005-07-05
影响因子：
11.1
通讯作者：
Fussenegger, M
中科院分区：
文献类型：
--
作者：
Kramer, BP;Fussenegger, M
双稳态和滞后开关使细胞能够响应单个外部输入信号而采取多种内部表达状态，对从细胞命运决定到细胞周期控制的生物系统产生关键影响。我们设计了一个合成的滞后哺乳动物转录网络。正反馈环路由转基因和反式激活子 (TA) 组成，TA 是由 TA 的同源启动子共同转录的，该环路受到大环内酯依赖性转录沉默子的组成型表达的抑制，该沉默子的活性由大环内酯类抗生素红霉素调节。发生转基因表达的准连续转换的抗生素浓度取决于合成转录回路的历史。如果网络组件不平衡，则会发生分级信号积分，而不是准不连续信号积分。这些发现与数学模型一致。能够模拟自然基因表达行为的合成基因网络可能会促进未来基因治疗和组织工程计划的进展。
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-cliscontinuous 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.