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تسجيل مستخدم جديدCell phenotypic transition proceeds through concerted reorganization of gene regulatory network
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Phenotype transition takes place in many biological processes such as differentiation, and understanding how a cell reprograms its global gene expression profile is a problem of rate theories. A cell phenotype transition accompanies with switching of expression rates of clusters of genes, analogous to domain flipping in an Ising system. Here through analyzing single cell RNA sequencing data in the framework of transition path theory, we set to study how such a genome-wide expression program switching proceeds in three different cell transition processes. For each process after reconstructing a Markov transition model in the cell state space, we formed an ensemble of shortest paths connecting the initial and final cell states, reconstructed a reaction coordinate describing the transition progression, and inferred the gene regulation network (GRN) along the reaction coordinate. In all three processes we observed common pattern that the frustration of gene regulatory network (GRN), defined as overall confliction between the regulation received by genes and their expression states, first increases then decreases when approaching a new phenotype. The results support a mechanism of concerted silencing of genes that are active in the initial phenotype and activation of genes that are active in the final phenotype.
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Gene regulatory networks (GRNs) control cellular function and decision making during tissue development and homeostasis. Mathematical tools based on dynamical systems theory are often used to model these networks, but the size and complexity of these
models mean that their behaviour is not always intuitive and the underlying mechanisms can be difficult to decipher. For this reason, methods that simplify and aid exploration of complex networks are necessary. To this end we develop a broadly applicable form of the Zwanzig-Mori projection. By first converting a thermodynamic state ensemble model of gene regulation into mass action reactions we derive a general method that produces a set of time evolution equations for a subset of components of a network. The influence of the rest of the network, the bulk, is captured by memory functions that describe how the subnetwork reacts to its own past state via components in the bulk. These memory functions provide probes of near-steady state dynamics, revealing information not easily accessible otherwise. We illustrate the method on a simple cross-repressive transcriptional motif to show that memory functions not only simplify the analysis of the subnetwork but also have a natural interpretation. We then apply the approach to a GRN from the vertebrate neural tube, a well characterised developmental transcriptional network composed of four interacting transcription factors. The memory functions reveal the function of specific links within the neural tube network and identify features of the regulatory structure that specifically increase the robustness of the network to initial conditions. Taken together, the study provides evidence that Zwanzig-Mori projections offer powerful and effective tools for simplifying and exploring the behaviour of GRNs.
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Genes and proteins regulate cellular functions through complex circuits of biochemical reactions. Fluctuations in the components of these regulatory networks result in noise that invariably corrupts the signal, possibly compromising function. Here, w
e create a practical formalism based on ideas introduced by Wiener and Kolmogorov (WK) for filtering noise in engineered communications systems to quantitatively assess the extent to which noise can be controlled in biological processes involving negative feedback. Application of the theory, which reproduces the previously proven scaling of the lower bound for noise suppression in terms of the number of signaling events, shows that a tetracycline repressor-based negative-regulatory gene circuit behaves as a WK filter. For the class of Hill-like nonlinear regulatory functions, this type of filter provides the optimal reduction in noise. Our theoretical approach can be readily combined with experimental measurements of response functions in a wide variety of genetic circuits, to elucidate the general principles by which biological networks minimize noise.
Gene transcription is a stochastic process mostly occurring in bursts. Regulation of transcription arises from the interaction of transcription factors (TFs) with the promoter of the gene. The TFs, such as activators and repressors can interact with
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