Department of Bioengineering and Department of Electrical Engineering, University of Texas at Dallas, Richardson, TX, USA.
Mol Syst Biol. 2011 Aug 2;7:519. doi: 10.1038/msb.2011.49.
Natural and synthetic biological networks must function reliably in the face of fluctuating stoichiometry of their molecular components. These fluctuations are caused in part by changes in relative expression efficiency and the DNA template amount of the network-coding genes. Gene product levels could potentially be decoupled from these changes via built-in adaptation mechanisms, thereby boosting network reliability. Here, we show that a mechanism based on an incoherent feedforward motif enables adaptive gene expression in mammalian cells. We modeled, synthesized, and tested transcriptional and post-transcriptional incoherent loops and found that in all cases the gene product adapts to changes in DNA template abundance. We also observed that the post-transcriptional form results in superior adaptation behavior, higher absolute expression levels, and lower intrinsic fluctuations. Our results support a previously hypothesized endogenous role in gene dosage compensation for such motifs and suggest that their incorporation in synthetic networks will improve their robustness and reliability.
自然和合成生物网络必须能够在其分子成分的化学计量比波动的情况下可靠地发挥功能。这些波动部分是由网络编码基因的相对表达效率和 DNA 模板数量的变化引起的。通过内置的适应机制，基因产物水平有可能与这些变化解耦，从而提高网络的可靠性。在这里，我们展示了一种基于非相干前馈模式的机制，使哺乳动物细胞中的基因表达具有适应性。我们对转录和转录后非相干环进行了建模、合成和测试，发现无论在何种情况下，基因产物都能适应 DNA 模板丰度的变化。我们还观察到，转录后形式表现出更好的适应行为、更高的绝对表达水平和更低的固有波动。我们的结果支持了先前关于这些模体在基因剂量补偿中的内源性作用的假设，并表明它们在合成网络中的引入将提高网络的鲁棒性和可靠性。
