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      Signal Manifestation Trade-offs in Incoherent Feed-Forward Loops

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          Abstract

          Signal processing in biological systems is delicately executed by specialised networks, which are modular assemblies of network motifs. The motifs are independently functional circuits found in enormous numbers in any living cell. A very common network motif is the feed-forward loop (FFL), which regulates a downstream node by an upstream one in a direct and an indirect way within the network. If the direct and indirect regulations go antagonistic, the motif is known as an incoherent FFL (ICFFL). The current study is aimed at exploring the reason for the variation in the evolutionary selection of the four types of ICFFLs. As comparative measures, I compute sensitivity amplification, adaptation precision and efficiency from the temporal dynamics and mutual information between the input-output nodes of the motifs at steady state. The ICFFL II performs very efficiently in adaptation but poor in information processing. On the other hand, ICFFL I and III are better in information transmission compared to adaptation efficiency. Which is the fittest among them under the pressure of natural selection? To sort out this puzzle, I take help from the multi-objective Pareto efficiency. The results, found in the Pareto task space, are in good agreement with the reported abundance level of all the types in eukaryotes as well as prokaryotes.

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          Structure and function of the feed-forward loop network motif.

          Engineered systems are often built of recurring circuit modules that carry out key functions. Transcription networks that regulate the responses of living cells were recently found to obey similar principles: they contain several biochemical wiring patterns, termed network motifs, which recur throughout the network. One of these motifs is the feed-forward loop (FFL). The FFL, a three-gene pattern, is composed of two input transcription factors, one of which regulates the other, both jointly regulating a target gene. The FFL has eight possible structural types, because each of the three interactions in the FFL can be activating or repressing. Here, we theoretically analyze the functions of these eight structural types. We find that four of the FFL types, termed incoherent FFLs, act as sign-sensitive accelerators: they speed up the response time of the target gene expression following stimulus steps in one direction (e.g., off to on) but not in the other direction (on to off). The other four types, coherent FFLs, act as sign-sensitive delays. We find that some FFL types appear in transcription network databases much more frequently than others. In some cases, the rare FFL types have reduced functionality (responding to only one of their two input stimuli), which may partially explain why they are selected against. Additional features, such as pulse generation and cooperativity, are discussed. This study defines the function of one of the most significant recurring circuit elements in transcription networks.
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            STOCHASTIC PROCESSES

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              The coherent feedforward loop serves as a sign-sensitive delay element in transcription networks.

              Recent analysis of the structure of transcription regulation networks revealed several "network motifs": regulatory circuit patterns that occur much more frequently than in randomized networks. It is important to understand whether these network motifs have specific functions. One of the most significant network motifs is the coherent feedforward loop, in which transcription factor X regulates transcription factor Y, and both jointly regulate gene Z. On the basis of mathematical modeling and simulations, it was suggested that the coherent feedforward loop could serve as a sign-sensitive delay element: a circuit that responds rapidly to step-like stimuli in one direction (e.g. ON to OFF), and at a delay to steps in the opposite direction (OFF to ON). Is this function actually carried out by feedforward loops in living cells? Here, we address this experimentally, using a system with feedforward loop connectivity, the L-arabinose utilization system of Escherichia coli. We measured responses to step-like cAMP stimuli at high temporal resolution and accuracy by means of green fluorescent protein reporters. We show that the arabinose system displays sign-sensitive delay kinetics. This type of kinetics is important for making decisions based on noisy inputs by filtering out fluctuations in input stimuli, yet allowing rapid response. This information-processing function may be performed by the feedforward loop regulation modules that are found in diverse systems from bacteria to humans.
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                Author and article information

                Journal
                2016-12-07
                Article
                1612.02116
                6bfb940d-ca99-4aa8-b1d0-782207104831

                http://arxiv.org/licenses/nonexclusive-distrib/1.0/

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                Custom metadata
                10 pages, 4 figures
                q-bio.MN

                Molecular biology
                Molecular biology

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