The incoherent feed‐forward loop can generate non‐monotonic input functions for genes

Gene regulation networks contain recurring circuit patterns called network motifs. One of the most common network motif is the incoherent type 1 feed‐forward loop (I1‐FFL), in which an activator controls both gene and repressor of that gene. This motif was shown to act as a pulse generator and response accelerator of gene expression. Here we consider an additional function of this motif: the I1‐FFL can generate a non‐monotonic dependence of gene expression on the input signal. Here, we study this experimentally in the galactose system of Escherichia coli, which is regulated by an I1‐FFL. The promoter activity of two of the gal operons, galETK and galP, peaks at intermediate levels of the signal cAMP. We find that mutants in which the I1‐FFL is disrupted lose this non‐monotonic behavior, and instead display monotonic input functions. Theoretical analysis suggests that non‐monotonic input functions can be achieved for a wide range of parameters by the I1‐FFL. The models also suggest regimes where a monotonic input‐function can occur, as observed in the mglBAC operon regulated by the same I1‐FFL. The present study thus experimentally demonstrates how upstream circuitry can affect gene input functions and how an I1‐FFL functions within its natural context in the cell.     

A DPP-mediated feed-forward loop canalizes morphogenesis during Drosophila dorsal closure

Development is robust because nature has selected various mechanisms to buffer the deleterious effects of environmental and genetic variations to deliver phenotypic stability. Robustness relies on smart network motifs such as feed-forward loops (FFLs) that ensure the reliable interpretation of developmental signals. In this paper, we show that Decapentaplegic (DPP) and JNK form a coherent FFL that controls the specification and differentiation of leading edge cells during Drosophila melanogaster dorsal closure (DC). We provide molecular evidence that through repression by Brinker (Brk), the DPP branch of the FFL filters unwanted JNK activity. High-throughput live imaging revealed that this DPP/Brk branch is dispensable for DC under normal conditions but is required when embryos are subjected to thermal stress. Our results indicate that the wiring of DPP signaling buffers against environmental challenges and canalizes cell identity. We propose that the main function of DPP pathway during Drosophila DC is to ensure robust morphogenesis, a distinct function from its well-established ability to spread spatial information.     

Evolutionary modelling of feed forward loops in gene regulatory networks

Feed forward loops (FFLs) are gene regulatory network motifs. They exist in different types, defined by the signs of the effects of genes in the motif on one another. We examine 36 feed forward loops in Escherichia coli, using evolutionary simulations to predict the forms of FFL expected to evolve to generate the pattern of expression of the output gene. These predictions are tested using likelihood ratios, comparing likelihoods of the observed FFL structures with their likelihoods under null models. The very high likelihood ratios generated, of over 10(11), suggest that evolutionary simulation is a valuable component in the explanation of FFL structure.     

Structural discrimination of robustness in transcriptional feedforward loops for pattern formation

Signaling pathways are interconnected to regulatory circuits for sensing the environment and expressing the appropriate genetic profile. In particular, gradients of diffusing molecules (morphogens) determine cell fate at a given position, dictating development and spatial organization. The feedforward loop (FFL) circuit is among the simplest genetic architectures able to generate one-stripe patterns by operating as an amplitude detection device, where high output levels are achieved at intermediate input ones. Here, using a heuristic optimization-based approach, we dissected the design space containing all possible topologies and parameter values of the FFL circuits. We explored the ability of being sensitive or adaptive to variations in the critical morphogen level where cell fate is switched. We found four different solutions for precision, corresponding to the four incoherent architectures, but remarkably only one mode for adaptiveness, the incoherent type 4 (I4-FFL). We further carried out a theoretical study to unveil the design principle for such structural discrimination, finding that the synergistic action and cooperative binding on the downstream promoter are instrumental to achieve absolute adaptive responses. Subsequently, we analyzed the robustness of these optimal circuits against perturbations in the kinetic parameters and molecular noise, which has allowed us to depict a scenario where adaptiveness, parameter sensitivity and noise tolerance are different, correlated facets of the robustness of the I4-FFL circuit. Strikingly, we showed a strong correlation between the input (environment-related) and the intrinsic (mutation-related) susceptibilities. Finally, we discussed the evolution of incoherent regulations in terms of multifunctionality and robustness.     

Cost-benefit theory and optimal design of gene regulation functions

Cells respond to the environment by regulating the expression of genes according to environmental signals. The relation between the input signal level and the expression of the gene is called the gene regulation function. It is of interest to understand the shape of a gene regulation function in terms of the environment in which it has evolved and the basic constraints of biological systems. Here we address this by presenting a cost-benefit theory for gene regulation functions that takes into account temporally varying inputs in the environment and stochastic noise in the biological components. We apply this theory to the well-studied lac operon of E. coli. The present theory explains the shape of this regulation function in terms of temporal variation of the input signals, and of minimizing the deleterious effect of cell-cell variability in regulatory protein levels. We also apply the theory to understand the evolutionary tradeoffs in setting the number of regulatory proteins and for selection of feed-forward loops in genetic circuits. The present cost-benefit theory can be used to understand the shape of other gene regulatory functions in terms of environment and noise constraints.     

Automatic design of digital synthetic gene circuits

De novo computational design of synthetic gene circuits that achieve well-defined target functions is a hard task. Existing, brute-force approaches run optimization algorithms on the structure and on the kinetic parameter values of the network. However, more direct rational methods for automatic circuit design are lacking. Focusing on digital synthetic gene circuits, we developed a methodology and a corresponding tool for in silico automatic design. For a given truth table that specifies a circuit's input-output relations, our algorithm generates and ranks several possible circuit schemes without the need for any optimization. Logic behavior is reproduced by the action of regulatory factors and chemicals on the promoters and on the ribosome binding sites of biological Boolean gates. Simulations of circuits with up to four inputs show a faithful and unequivocal truth table representation, even under parametric perturbations and stochastic noise. A comparison with already implemented circuits, in addition, reveals the potential for simpler designs with the same function. Therefore, we expect the method to help both in devising new circuits and in simplifying existing solutions.     

水稻抗逆相关基因的分子进化分析

植物在进化过程中为了适应外界环境,已经具有一套完整的抵抗外界特殊环境的调控系统。但是,关于水稻抗逆相关基因的分子进化方面的研究还未见报道。文章通过Plant Tolerance Gene Database数据库,获得22个水稻抗逆相关基因。利用比较基因组学和生物信息学方法对水稻抗逆相关基因的进化动态进行研究,结果表明水稻抗逆相关基因在低等植物中比较保守;随着植物的不断进化和生存环境的改变,其基因数量也随之增加。具有相似抗性功能的基因往往具有相似的基因结构和基序(motif)结构。文章还发现4个保守motif 的存在：HRDXK、DXXSXG、LLPR和GXGXXG(X代表任意氨基酸)。在GSK1、RAN2抗逆基因中发现了3个特有的motif结构：GSK1特有的P-rich motif,RAN2特有的G-rich motif和E-rich motif。推测这些保守的motif结构与基因的抗逆功能密切相关。进化速率分析结果表明,尽管植物抗逆性相关基因在进化过程中受到较强的纯化选择作用,但是仍然有50%的抗逆性相关基因存在正选择位点。这些正选择位点的存在有可能为基因适应外界环境变化提供了重要的物质基础。     

Automatic Adaptation to Fast Input Changes in a Time-Invariant Neural Circuit

Neurons must faithfully encode signals that can vary over many orders of magnitude despite having only limited dynamic ranges. For a correlated signal, this dynamic range constraint can be relieved by subtracting away components of the signal that can be predicted from the past, a strategy known as predictive coding, that relies on learning the input statistics. However, the statistics of input natural signals can also vary over very short time scales e.g., following saccades across a visual scene. To maintain a reduced transmission cost to signals with rapidly varying statistics, neuronal circuits implementing predictive coding must also rapidly adapt their properties. Experimentally, in different sensory modalities, sensory neurons have shown such adaptations within 100 ms of an input change. Here, we show first that linear neurons connected in a feedback inhibitory circuit can implement predictive coding. We then show that adding a rectification nonlinearity to such a feedback inhibitory circuit allows it to automatically adapt and approximate the performance of an optimal linear predictive coding network, over a wide range of inputs, while keeping its underlying temporal and synaptic properties unchanged. We demonstrate that the resulting changes to the linearized temporal filters of this nonlinear network match the fast adaptations observed experimentally in different sensory modalities, in different vertebrate species. Therefore, the nonlinear feedback inhibitory network can provide automatic adaptation to fast varying signals, maintaining the dynamic range necessary for accurate neuronal transmission of natural inputs.     

Parameter asymmetry and time-scale separation in core genetic commitment circuits

Theory allows studying why Evolution might select core genetic commitment circuit topologies over alternatives. The nonlinear dynamics of the underlying gene regulation together with the unescapable subtle interplay of intrinsic biochemical noise impact the range of possible evolutionary choices. The question of why certain genetic regulation circuits might present robustness to phenotype-delivery breaking over others, is therefore of high interest. Here, the behavior of systematically more complex commitment circuits is studied, in the presence of intrinsic noise, with a focus on two aspects relevant to biology: parameter asymmetry and time-scale separation. We show that phenotype delivery is broken in simple two- and three-gene circuits. In the two-gene circuit, we show how stochastic potential wells of different depths break commitment. In the three-gene circuit, we show that the onset of oscillations breaks the commitment phenotype in a systematic way. Finally, we also show that higher dimensional circuits (four-gene and five-gene circuits) may be intrinsically more robust.