Krishnan J, Floros Ioannis
Department of Chemical Engineering, Centre for Process Systems Engineering, Imperial College London, South Kensington, London, SW7 2AZ, UK.
National Centre of Scientific Research "Demokritos", Athens, Greece.
BMC Syst Biol. 2019 Mar 14;13(1):32. doi: 10.1186/s12918-019-0703-1.
Adaptation and homeostasis are basic features of information processing in cells and seen in a broad range of contexts. Much of the current understanding of adaptation in network modules/motifs is based on their response to simple stimuli. Recently, there have also been studies of adaptation in dynamic stimuli. However a broader synthesis of how different circuits of adaptation function, and which circuits enable a broader adaptive behaviour in classes of more complex and spatial stimuli is largely missing.
We study the response of a variety of adaptive circuits to time-varying stimuli such as ramps, periodic stimuli and static and dynamic spatial stimuli. We find that a variety of responses can be seen in ramp stimuli, making this a basis for discriminating between even similar circuits. We also find that a number of circuits adapt exactly to ramp stimuli, and dissect these circuits to pinpoint what characteristics (architecture, feedback, biochemical aspects, information processing ingredients) allow for this. These circuits include incoherent feedforward motifs, inflow-outflow motifs and transcritical circuits. We find that changes in location in such circuits where a signal acts can result in non-adaptive behaviour in ramps, even though the location was associated with exact adaptation in step stimuli. We also demonstrate that certain augmentations of basic inflow-outflow motifs can alter the behaviour of the circuit from exact adaptation to non-adaptive behaviour. When subject to periodic stimuli, some circuits (inflow-outflow motifs and transcritical circuits) are able to maintain an average output independent of the characteristics of the input. We build on this to examine the response of adaptive circuits to static and dynamic spatial stimuli. We demonstrate how certain circuits can exhibit a graded response in spatial static stimuli with an exact maintenance of the spatial mean-value. Distinct features which emerge from the consideration of dynamic spatial stimuli are also discussed. Finally, we also build on these results to show how different circuits which show any combination of presence or absence of exact adaptation in ramps, exact mainenance of time average output in periodic stimuli and exact maintenance of spatial average of output in static spatial stimuli may be realized.
By studying a range of network circuits/motifs on one hand and a range of stimuli on the other, we isolate characteristics of these circuits (structural) which enable different degrees of exact adaptive and homeostatic behaviour in such stimuli, how they may be combined, and also identify cases associated with non-homeostatic behaviour. We also reveal constraints associated with locations where signals may act to enable homeostatic behaviour and constraints associated with augmentations of circuits. This consideration of multiple experimentally/naturally relevant stimuli along with circuits of adaptation of relevance in natural and engineered biology, provides a platform for deepening our understanding of adaptive and homeostatic behaviour in natural systems, bridging the gap between models of adaptation and experiments and in engineering homeostatic synthetic circuits.
适应和稳态是细胞信息处理的基本特征，在广泛的背景中都能看到。目前对网络模块/基序中适应的理解大多基于它们对简单刺激的反应。最近，也有关于动态刺激中适应的研究。然而，对于不同的适应回路如何发挥作用，以及哪些回路能在更复杂的空间刺激类别中实现更广泛的适应性行为，在很大程度上仍缺乏更全面的综合研究。
我们研究了各种适应回路对随时间变化的刺激（如斜坡、周期性刺激以及静态和动态空间刺激）的反应。我们发现斜坡刺激中能观察到多种反应，这使其成为区分甚至相似回路的基础。我们还发现一些回路能精确适应斜坡刺激，并剖析这些回路以确定哪些特征（结构、反馈、生化方面、信息处理要素）使其具备这种能力。这些回路包括非相干前馈基序、流入 - 流出基序和跨临界回路。我们发现，在这些回路中信号起作用的位置发生变化会导致在斜坡刺激中出现非适应性行为，尽管该位置在阶跃刺激中与精确适应相关。我们还证明，对基本流入 - 流出基序的某些增强可以改变回路的行为，使其从精确适应变为非适应性行为。当受到周期性刺激时，一些回路（流入 - 流出基序和跨临界回路）能够保持平均输出，而与输入的特征无关。在此基础上，我们研究了适应回路对静态和动态空间刺激的反应。我们展示了某些回路如何在空间静态刺激中表现出分级反应，并精确维持空间平均值。还讨论了从动态空间刺激的考虑中出现的不同特征。最后，我们还基于这些结果展示了如何实现不同的回路，这些回路在斜坡刺激中表现出精确适应与否、在周期性刺激中精确维持时间平均输出以及在静态空间刺激中精确维持输出的空间平均值的任意组合。
一方面通过研究一系列网络回路/基序，另一方面通过研究一系列刺激，我们分离出了这些回路的特征（结构），这些特征能在这些刺激中实现不同程度的精确适应和稳态行为、它们如何组合，还识别出了与非稳态行为相关的情况。我们还揭示了与信号可能起作用以实现稳态行为的位置相关的限制以及与回路增强相关的限制。对多种实验/自然相关刺激以及自然和工程生物学中相关适应回路的这种考虑，为深化我们对自然系统中适应和稳态行为的理解提供了一个平台，弥合了适应模型与实验之间的差距，并为工程化稳态合成回路提供了支持。
