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Register a new userA Reaction-Diffusion Model of the Cadherin-Catenin System: A Possible Mechanism for Contact Inhibition and Implications for Tumorigenesis
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Contact inhibition is the process by which cells switch from a motile growing state to a passive and stabilized state upon touching their neighbors. When two cells touch, an adhesion link is created between them by means of transmembrane E-cadherin proteins. Simultaneously, their actin filaments stop polymerizing in the direction perpendicular to the membrane and reorganize to create an apical belt that colocalizes with the adhesion links. Here, we propose a detailed quantitative model of the role of the cytoplasmic $beta$-catenin and $alpha$-catenin proteins in this process, treated as a reaction-diffusion system. Upon cell-cell contact, the concentration in $alpha$-catenin dimers increases, inhibiting actin branching and thereby reducing cellular motility and expansion pressure. This model provides a mechanism for contact inhibition that could explain previously unrelated experimental findings on the role played by E-cadherin, $beta$-catenin and $alpha$-catenin in the cellular phenotype and in tumorigenesis. In particular, we address the effect of a knockout of the adenomatous polyposis coli tumor suppressor gene. Potential direct tests of our model are discussed.
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Current models for the folding of the human genome see a hierarchy stretching down from chromosome territories, through A/B compartments and TADs (topologically-associating domains), to contact domains stabilized by cohesin and CTCF. However, molecular mechanisms underlying this folding, and the way folding affects transcriptional activity, remain obscure. Here we review physical principles driving proteins bound to long polymers into clusters surrounded by loops, and present a parsimonious yet comprehensive model for the way the organization determines function. We argue that clusters of active RNA polymerases and their transcription factors are major architectural features; then, contact domains, TADs, and compartments just reflect one or more loops and clusters. We suggest tethering a gene close to a cluster containing appropriate factors -- a transcription factory -- increases the firing frequency, and offer solutions to many current puzzles concerning the actions of enhancers, super-enhancers, boundaries, and eQTLs (expression quantitative trait loci). As a result, the activity of any gene is directly influenced by the activity of other transcription units around it in 3D space, and this is supported by Brownian-dynamics simulations of transcription factors binding to cognate sites on long polymers.
Robustness of spatial pattern against perturbations is an indispensable property of developmental processes for organisms, which need to adapt to changing environments. Although specific mechanisms for this robustness have been extensively investigated, little is known about a general mechanism for achieving robustness in reaction-diffusion systems. Here, we propose a buffered reaction-diffusion system, in which active states of chemicals mediated by buffer molecules contribute to reactions, and demonstrate that robustness of the pattern wavelength is achieved by the dynamics of the buffer molecule. This robustness is analytically explained as a result of the scaling properties of the buffered system, which also lead to a reciprocal relationship between the wavelengths robustness and the plasticity of the spatial phase upon external perturbations. Finally, we explore the relevance of this reciprocity to biological systems.
Membrane tubes are important elements for living cells to organize many functions. Experiments have found that membrane tube can be extracted from giant lipid vesicles by a group of kinesin. How these motors cooperate in extracting the fluid-like membrane tube is still unclear. In this paper, we propose a new cooperation mechanism called two-track-dumbbell model, in which kinesin is regarded as a dumbbell with an end (tail domain) tightly bound onto the fluid-like membrane and the other end (head domain) stepping on or unbinding from the microtubule. Taking account of the elasticity of kinesin molecule and the exclude volume effect of both the head domain and the tail domain of kinesin, which are not considered in previous models, we simulate the growth process of the membrane tube pulled by kinesin motors. Our results indicate that motors along a single microtubule protofilament can generate enough force to extract membrane tubes from vesicles, and the average number of motors pulling the tube is about 8~9. These results are quite different from previous studies (Ref. cite{camp.08}), and further experimental tests are necessary to elucidate the cooperation mechanism.
Switching of the direction of flagella rotations is the key control mechanism governing the chemotactic activity of E. coli and many other bacteria. Power-law distributions of switching times are most peculiar because their emergence cannot be deduced from simple thermodynamic arguments. Recently it was suggested that by adding finite-time correlations into Gaussian fluctuations regulating the energy height of barrier between the two rotation states, one can generate a power-law switching statistics. By using a simple model of a regulatory pathway, we demonstrate that the required amount of correlated `noise can be produced by finite number fluctuations of reacting protein molecules, a condition common to the intracellular chemistry. The corresponding power-law exponent appears as a tunable characteristic controlled by parameters of the regulatory pathway network such as equilibrium number of molecules, sensitivities, and the characteristic relaxation time.
We propose a stochastic model for gene transcription coupled to DNA supercoiling, where we incorporate the experimental observation that polymerases create supercoiling as they unwind the DNA helix, and that these enzymes bind more favourably to regions where the genome is unwound. Within this model, we show that when the transcriptionally induced flux of supercoiling increases, there is a sharp crossover from a regime where torsional stresses relax quickly and gene transcription is random, to one where gene expression is highly correlated and tightly regulated by supercoiling. In the latter regime, the model displays transcriptional bursts, waves of supercoiling, and up-regulation of divergent or bidirectional genes. It also predicts that topological enzymes which relax twist and writhe should provide a pathway to down-regulate transcription. This article has been published in Physical Review Letters, May 2016.
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