Background Regulation of gene expression is of paramount importance in all living systems. In the past two decades, it has been discovered that certain motifs, such as the feedforward motif, are overrepresented in gene regulatory circuits. Feedforward loops are also ubiquitous in process control engineering, and are nearly always structured so that one branch has the opposite effect of the other, which is a structure known as an "incoherent" feedforward loop in biology. In engineered systems, feedforward control loops are subject to several engineering constraints, including that (1) they are finely-tuned so that the system returns to the original steady state after a disturbance occurs (perfect adaptation), (2) they are typically only implemented in the combination with negative feedback, and (3) they can greatly improve the stability and dynamical characteristics of the conjoined negative feedback loop. On the other hand, in biology, incoherent feedforward loops can serve many purposes, one of which may be perfect adaptation. It is an open question as to whether those that achieve perfect adaptation are subject to the above engineering principles. Results We analyzed an incoherent feedforward gene regulatory motif from the standpoint of the above engineering principles. In particular, we showed that an incoherent feedforward loop Type 1 (I1-FFL), from within a gene regulatory circuit, can be finely-tuned for perfect adaptation after a stimulus, and that the robustness of this behavior is increased by the presence of moderate negative feedback. In addition, we analyzed the advantages of adding a feedforward loop to a system that already operated under negative feedback, and found that the dynamical properties of the combined feedforward/feedback system were superior. Conclusions Our analysis shows that many of the engineering principles used in engineering design of feedforward control are also applicable to feedforward loops in biological systems. We speculate that principles found in other domains of engineering may also be applicable to analogous structures in biology.

中文翻译：

---

将转录不连贯的前馈循环与负反馈相结合的工程原理。

背景 基因表达的调控在所有生命系统中都至关重要。在过去的二十年中，人们发现某些基序，例如前馈基序，在基因调控电路中的比例过高。前馈回路在过程控制工程中也无处不在，并且几乎总是结构化，使得一个分支具有另一个分支的相反效果，这是一种在生物学中被称为“不连贯”前馈回路的结构。在工程系统中，前馈控制回路受到几个工程约束，包括（1）它们经过微调，以便系统在发生干扰后恢复到原始稳态（完美适应），（2）它们通常只结合负反馈实施，(3)它们可以大大提高联合负反馈回路的稳定性和动态特性。另一方面，在生物学中，不连贯的前馈循环可以服务于许多目的，其中一个可能是完美的适应。那些达到完美适应的人是否受制于上述工程原理，这是一个悬而未决的问题。结果我们从上述工程原理的角度分析了一个不连贯的前馈基因调控基序。特别是，我们表明，来自基因调控电路内的不连贯前馈环 1 型 (I1-FFL) 可以在刺激后进行微调以实现完美适应，并且这种行为的鲁棒性因存在中度负反馈。此外，我们分析了向已经在负反馈下运行的系统添加前馈回路的优势，发现组合前馈/反馈系统的动态特性更优越。结论 我们的分析表明，前馈控制工程设计中使用的许多工程原理也适用于生物系统中的前馈回路。我们推测在其他工程领域发现的原理也可能适用于生物学中的类似结构。