Nakamura Eiji, Blanchini Franco, Giordano Giulia, Hoffmann Alexander, Franco Elisa
Department of Mechanical and Aerospace Engineering, University of California, Los Angeles, USA.
Department of Mathematics, Computer Science and Physics, University of Udine, Italy.
bioRxiv. 2025 Feb 11:2025.02.10.636967. doi: 10.1101/2025.02.10.636967.
Cells have the capacity to encode and decode information in the temporal features of molecular signals. Many pathways, for example, generate either sustained or pulsatile responses depending on the context, and such diverse temporal behaviors have a profound impact on cell fate. Here we focus on how molecular pathways can convert the temporal features of dynamic signals, in particular how they can convert transient signals into persistent downstream events and vice versa. We describe this type of behavior as temporal dose inversion, and we demonstrate that it can be achieved through adaptive molecular circuits. We consider motifs known as incoherent feedforward loop (IFFL) and negative feedback loop (NFL), and identify parametric conditions that enable temporal dose inversion. We next consider more complex versions of these circuits that could be realized using enzymatic signaling and gene regulatory networks, finding that both circuits can exhibit temporal dose inversion. Finally, we consider a generalized IFFL topology, and we find that both the time delay in the inhibition pathway and the relative signal intensities of the activation and inhibition signals are key determinants for temporal dose inversion. Our investigation expands the potential use of adaptive circuits as signal processing units and contributes to our understanding of the role of adaptive circuits in nature.
细胞有能力对分子信号的时间特征中的信息进行编码和解码。例如，许多信号通路会根据具体情况产生持续或脉动反应，而这种多样的时间行为对细胞命运有着深远影响。在这里，我们关注分子信号通路如何转换动态信号的时间特征，特别是它们如何将瞬态信号转换为持续的下游事件，反之亦然。我们将这种行为类型描述为时间剂量反转，并证明它可以通过适应性分子回路来实现。我们考虑了被称为非相干前馈环（IFFL）和负反馈环（NFL）的基序，并确定了能够实现时间剂量反转的参数条件。接下来，我们考虑这些回路更复杂的版本，它们可以通过酶促信号传导和基因调控网络来实现，发现这两种回路都可以表现出时间剂量反转。最后，我们考虑一种广义的IFFL拓扑结构，发现抑制通路中的时间延迟以及激活和抑制信号的相对信号强度都是时间剂量反转的关键决定因素。我们的研究扩展了适应性回路作为信号处理单元的潜在用途，并有助于我们理解适应性回路在自然界中的作用。
