Multiple binding sites for transcriptional repressors can produce regular bursting and enhance noise suppression

Cells may control fluctuations in protein levels by means of negative autoregulation, where transcription factors bind DNA sites to repress their own production. Theoretical studies have assumed a single binding site for the repressor, while in most species it is found that multiple binding sites are arranged in clusters. We study a stochastic description of negative autoregulation with multiple binding sites for the repressor. We find that increasing the number of binding sites induces regular bursting of gene products. By tuning the threshold for repression, we show that multiple binding sites can also suppress fluctuations. Our results highlight possible roles for the presence of multiple binding sites of negative autoregulators

Associative memory on a small-world neural network

We study a model of associative memory based on a neural network with small-world structure. The efficacy of the network to retrieve one of the stored patterns exhibits a phase transition at a finite value of the disorder. The more ordered networks are unable to recover the patterns, and are always attracted to mixture states. Besides, for a range of the number of stored patterns, the efficacy has a maximum at an intermediate value of the disorder. We also give a statistical characterization of the attractors for all values of the disorder of the network.Comment: 5 pages, 4 figures (eps

A framework for quantification and physical modeling of cell mixing applied to oscillator synchronization in vertebrate somitogenesis

In development and disease, cells move as they exchange signals. One example is found in vertebrate development, during which the timing of segment formation is set by a ‘segmentation clock’, in which oscillating gene expression is synchronized across a population of cells by Delta-Notch signaling. Delta-Notch signaling requires local cell-cell contact, but in the zebrafish embryonic tailbud, oscillating cells move rapidly, exchanging neighbors. Previous theoretical studies proposed that this relative movement or cell mixing might alter signaling and thereby enhance synchronization. However, it remains unclear whether the mixing timescale in the tissue is in the right range for this effect, because a framework to reliably measure the mixing timescale and compare it with signaling timescale is lacking. Here, we develop such a framework using a quantitative description of cell mixing without the need for an external reference frame and constructing a physical model of cell movement based on the data. Numerical simulations show that mixing with experimentally observed statistics enhances synchronization of coupled phase oscillators, suggesting that mixing in the tailbud is fast enough to affect the coherence of rhythmic gene expression. Our approach will find general application in analyzing the relative movements of communicating cells during development and disease.Fil: Uriu, Koichiro. Kanazawa University; JapónFil: Bhavna, Rajasekaran. Max Planck Institute of Molecular Cell Biology and Genetics; Alemania. Max Planck Institute for the Physics of Complex Systems; AlemaniaFil: Oates, Andrew C.. Francis Crick Institute; Reino Unido. University College London; Reino UnidoFil: Morelli, Luis Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Max Planck Institute for Molecular Physiology; Alemania. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Física; Argentin

Nonlinearity arising from noncooperative transcription factor binding enhances negative feedback and promotes genetic oscillations

We study the effects of multiple binding sites in the promoter of a genetic oscillator. We evaluate the regulatory function of a promoter with multiple binding sites in the absence of cooperative binding, and consider different hypotheses for how the number of bound repressors affects transcription rate. Effective Hill exponents of the resulting regulatory functions reveal an increase in the nonlinearity of the feedback with the number of binding sites. We identify optimal configurations that maximize the nonlinearity of the feedback. We use a generic model of a biochemical oscillator to show that this increased nonlinearity is reflected in enhanced oscillations, with larger amplitudes over wider oscillatory ranges. Although the study is motivated by genetic oscillations in the zebrafish segmentation clock, our findings may reveal a general principle for gene regulation.Comment: 11 pages, 8 figure

Synchronization in the presence of distributed delays

We study systems of identical coupled oscillators introducing a distribution of delay times in the coupling. For arbitrary network topologies, we show that the frequency and stability of the fully synchronized states depend only on the mean of the delay distribution. However, synchronization dynamics is sensitive to the shape of the distribution. In the presence of coupling delays, the synchronization rate can be maximal for a specific value of the coupling strength.Comment: 6 pages, 3 figure

Optimal cellular mobility for synchronization arising from the gradual recovery of intercellular interactions

Cell movement and intercellular signaling occur simultaneously during the development of tissues, but little is known about how movement affects signaling. Previous theoretical studies have shown that faster moving cells favor synchronization across a population of locally coupled genetic oscillators. An important assumption in these studies is that cells can immediately interact with their new neighbors after arriving at a new location. However, intercellular interactions in cellular systems may need some time to become fully established. How movement affects synchronization in this situation has not been examined. Here we develop a coupled phase oscillator model in which we consider cell movement and the gradual recovery of intercellular coupling experienced by a cell after movement, characterized by a moving rate and a coupling recovery rate respectively. We find (1) an optimal moving rate for synchronization, and (2) a critical moving rate above which achieving synchronization is not possible. These results indicate that the extent to which movement enhances synchrony is limited by a gradual recovery of coupling. These findings suggest that the ratio of time scales of movement and signaling recovery is critical for information transfer between moving cells.Comment: 18 single column pages + 1 table + 5 figures + Supporting Informatio

Self-propelled particles with fluctuating speed and direction of motion

We study general aspects of active motion with fluctuations in the speed and the direction of motion in two dimensions. We consider the case in which fluctuations in the speed are not correlated to fluctuations in the direction of motion, and assume that both processes can be described by independent characteristic time-scales. We show the occurrence of a complex transient that can exhibit a series of alternating regimes of motion, for two different angular dynamics which correspond to persistent and directed random walks. We also show additive corrections to the diffusion coefficient. The characteristic time-scales are also exposed in the velocity autocorrelation, which is a sum of exponential forms.Comment: to appear in Phys. Rev. Let

Intermittent ERK oscillations downstream of FGF in mouse embryonic stem cells

Signal transduction networks generate characteristic dynamic activities to process extracellular signals and guide cell fate decisions such as to divide or differentiate. The differentiation of pluripotent cells is controlled by FGF/ERK signaling. However, only a few studies have addressed the dynamic activity of the FGF/ERK signaling network in pluripotent cells at high time resolution. Here, we use live cell sensors in wild-type and Fgf4-mutant mouse embryonic stem cells to measure dynamic ERK activity in single cells, for defined ligand concentrations and differentiation states. These sensors reveal pulses of ERK activity. Pulsing patterns are heterogeneous between individual cells. Consecutive pulse sequences occur more frequently than expected from simple stochastic models. Sequences become more prevalent with higher ligand concentration, but are rarer in more differentiated cells. Our results suggest that FGF/ERK signaling operates in the vicinity of a transition point between oscillatory and non-oscillatory dynamics in embryonic stem cells. The resulting heterogeneous dynamic signaling activities add a new dimension to cellular heterogeneity that may be linked to divergent fate decisions in stem cell cultures.Fil: Raina, Dhruv. Institut Max Planck fur Molekulare Physiologie; AlemaniaFil: Fabris, Fiorella. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaFil: Morelli, Luis Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Institut Max Planck fur Molekulare Physiologie; AlemaniaFil: Schroter, Christian. Institut Max Planck fur Molekulare Physiologie; Alemani