Biomedical subjects

Juan F Poyatos

Publications and source records attributed to Juan F Poyatos.

5 recordsLinked to original sources

PubMed2006

Autogenous and nonautogenous control of response in a genetic network.

Feedback-based control methods determine the behavior of cellular systems, an example being autogenous control, the regulation of production of a protein by itself. This control strategy was theoretically shown to be superior to an equivalent but nonautogenously regulated system when based on a repressor. Although some of its advantages were later confirmed with isolated synthetic circuits, the superiority of autogenous control in natural networks remains untested. Here, we use the SOS DNA repair system of Escherichia coli, where autogenous control is part of a single-input module, as a valid model to evaluate the functional advantages and biological implications of this mechanism. We redesign the control of its master regulator, the protein LexA, so that it becomes nonautogenously controlled. We compare both systems by combining high-resolution expression measurements with mathematical modeling. We show that the stronger stability associated with the autogenous regulation prevents false triggering of the response due to transient fluctuations in the inducing signal and that this control also reduces the system recovery time at low DNA damage. Likewise, autoregulation produces responses proportional to the damage signal level. In contrast, bacteria with LexA constitutively expressed induce maximal action even for very low damage levels. This excess in response comes at a cost, because it reduces comparatively the growth rate of these cells. Our results suggest that autogenous control evolved as a strategy to optimally respond to multiple levels of input signal minimizing the costs of the response and highlights reasons why master regulators of single-input modules are mostly autorepressed.

Bacterial Proteins↗

PubMed2006

Is optimal gene order impossible?

Recent evidence suggests that yeast genes encoding proteins that are present in the same protein complex tend to be linked and to be co-expressed. More generally, we found that genes that are close to each other in the protein interaction network tend to be linked more often than expected and are often co-expressed. Unexpectedly, we found that linked genes in network proximity have unusually high recombination rates. Because high recombination rates are associated with high rates of genome re-organization, our findings might explain why the clustering of genes in proximity in the network is such a weak effect: there could be a co-evolutionary cycle of physical linkage for co-expression, upwards modification of the recombination rate and concomitant break-up of a cluster. Under such a model an "optimal" gene order is never stable.

Evolution, Molecular↗

PubMed2006

Dynamical principles of two-component genetic oscillators.

Genetic oscillators based on the interaction of a small set of molecular components have been shown to be involved in the regulation of the cell cycle, the circadian rhythms, or the response of several signaling pathways. Uncovering the functional properties of such oscillators then becomes important for the understanding of these cellular processes and for the characterization of fundamental properties of more complex clocks. Here, we show how the dynamics of a minimal two-component oscillator is drastically affected by its genetic implementation. We consider a repressor and activator element combined in a simple logical motif. While activation is always exerted at the transcriptional level, repression is alternatively operating at the transcriptional (Design I) or post-translational (Design II) level. These designs display differences on basic oscillatory features and on their behavior with respect to molecular noise or entrainment by periodic signals. In particular, Design I induces oscillations with large activator amplitudes and arbitrarily small frequencies, and acts as an "integrator" of external stimuli, while Design II shows emergence of oscillations with finite, and less variable, frequencies and smaller amplitudes, and detects better frequency-encoded signals ("resonator"). Similar types of stimulus response are observed in neurons, and thus this work enables us to connect very different biological contexts. These dynamical principles are relevant for the characterization of the physiological roles of simple oscillator motifs, the understanding of core machineries of complex clocks, and the bio-engineering of synthetic oscillatory circuits.

Animals↗

PubMed2004

How biologically relevant are interaction-based modules in protein networks?

By applying a graph-based algorithm to yeast protein-interaction networks we have extracted modular structures and show that they can be validated using information from the phylogenetic conservation of the network components. We show that the module cores, the parts with the highest intramodular connectivity, are biologically relevant components of the networks. These constituents correlate only weakly with other levels of organization. We also discuss how such structures could be used for finding targets for antimicrobial drugs.

Algorithms↗

PubMed2004

Non-neutral role of replicative senescence in tissue homeostasis and tumorigenesis.

Normal somatic cells divide only a limited number of times reaching a state known as replicative senescence. This restraint in reproductive potential has been proposed as a mechanism evolved in higher eukaryotes to protect the organism from developing cancer. However, despite this protection there is a positive correlation between tumor incidence and organism aging when cells are potentially closer to their replication limit. We use simple mathematical models derived from quasispecies theory to analyse the role of senescence in various scenarios with different cell types according to their replicative capacity. The models predict that a situation with cells launching more often the senescence response plays against tissue homeostasis favoring tumor initiation. It is also shown that cancer cells arising early in organism life are more sensitive to genetic instabilities progressing less often toward tissue invasion. The passage of cells through crisis emerges as a mechanism to maintain tissue homeostasis that is weakened in aged individuals. The models introduced, though simple, help to integrate experimental information relating tumorigenesis with cellular and organism aging phenomena.

Animals↗