Rahi Sahand Jamal, Larsch Johannes, Pecani Kresti, Katsov Alexander Y, Mansouri Nahal, Tsaneva-Atanasova Krasimira, Sontag Eduardo D, Cross Frederick R
Laboratory of Cell Cycle Genetics, The Rockefeller University, New York, New York, USA.
Center for Studies in Physics and Biology, The Rockefeller University, New York, New York, USA.
Nat Methods. 2017 Oct;14(10):1010-1016. doi: 10.1038/nmeth.4408. Epub 2017 Aug 28.
Biology emerges from interactions between molecules, which are challenging to elucidate with current techniques. An orthogonal approach is to probe for 'response signatures' that identify specific circuit motifs. For example, bistability, hysteresis, or irreversibility are used to detect positive feedback loops. For adapting systems, such signatures are not known. Only two circuit motifs generate adaptation: negative feedback loops (NFLs) and incoherent feed-forward loops (IFFLs). On the basis of computational testing and mathematical proofs, we propose differential signatures: in response to oscillatory stimulation, NFLs but not IFFLs show refractory-period stabilization (robustness to changes in stimulus duration) or period skipping. Applying this approach to yeast, we identified the circuit dominating cell cycle timing. In Caenorhabditis elegans AWA neurons, which are crucial for chemotaxis, we uncovered a Ca NFL leading to adaptation that would be difficult to find by other means. These response signatures allow direct access to the outlines of the wiring diagrams of adapting systems.
生物学源于分子间的相互作用，而利用当前技术阐明这些相互作用颇具挑战。一种正交方法是探寻可识别特定电路基序的“响应特征”。例如，双稳性、滞后现象或不可逆性被用于检测正反馈回路。对于适应性系统，此类特征尚不为人所知。仅有两种电路基序可产生适应性：负反馈回路（NFLs）和非相干前馈回路（IFFLs）。基于计算测试和数学证明，我们提出了差异特征：在响应振荡刺激时，NFLs而非IFFLs表现出不应期稳定（对刺激持续时间变化具有鲁棒性）或周期跳跃。将此方法应用于酵母，我们确定了主导细胞周期定时的电路。在对趋化作用至关重要的秀丽隐杆线虫AWA神经元中，我们发现了一个导致适应性的钙NFL，而通过其他方法很难找到它。这些响应特征使我们能够直接了解适应性系统布线图的轮廓。
