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Biomedical subjects

Jose M G Vilar

Publications and source records attributed to Jose M G Vilar.

8 recordsLinked to original sources
PubMed2006

Multiprotein DNA looping.

DNA looping plays a fundamental role in a wide variety of biological processes, providing the backbone for long range interactions on DNA. Here we develop the first model for DNA looping by an arbitrarily large number of proteins and solve it analytically in the case of identical binding. We uncover a switchlike transition between looped and unlooped phases and identify the key parameters that control this transition. Our results establish the basis for the quantitative understanding of fundamental cellular processes like DNA recombination, gene silencing, and telomere maintenance.

Binding Sites↗
PubMed2006

DNA looping: the consequences and its control.

The formation of DNA loops by proteins and protein complexes is ubiquitous to many fundamental cellular processes, including transcription, recombination and replication. Recently, advances have been made in understanding the properties of DNA looping in its natural context and how they propagate to cellular behavior through gene regulation. The result of connecting the molecular properties of DNA looping with cellular physiology measurements indicates that looping of DNA in vivo is much more complex and easier than predicted from current models, and reveals a wealth of previously unappreciated details.

Cell Physiological Phenomena↗
PubMed2006

Stochastic dynamics of macromolecular-assembly networks.

The formation and regulation of macromolecular complexes provides the backbone of most cellular processes, including gene regulation and signal transduction. The inherent complexity of assembling macromolecular structures makes current computational methods strongly limited for understanding how the physical interactions between cellular components give rise to systemic properties of cells. Here, we present a stochastic approach to study the dynamics of networks formed by macromolecular complexes in terms of the molecular interactions of their components. Exploiting key thermodynamic concepts, this approach makes it possible to both estimate reaction rates and incorporate the resulting assembly dynamics into the stochastic kinetics of cellular networks. As prototype systems, we consider the lac operon and phage lambda induction switches, which rely on the formation of DNA loops by proteins and on the integration of these protein-DNA complexes into intracellular networks. This cross-scale approach offers an effective starting point to move forward from network diagrams, such as those of protein-protein and DNA-protein interaction networks, to the actual dynamics of cellular processes.

Computational Biology↗
PubMed2006

Signal processing in the TGF-beta superfamily ligand-receptor network.

The TGF-beta pathway plays a central role in tissue homeostasis and morphogenesis. It transduces a variety of extracellular signals into intracellular transcriptional responses that control a plethora of cellular processes, including cell growth, apoptosis, and differentiation. We use computational modeling to show that coupling of signaling with receptor trafficking results in a highly versatile signal-processing unit, able to sense by itself absolute levels of ligand, temporal changes in ligand concentration, and ratios of multiple ligands. This coupling controls whether the response of the receptor module is transient or permanent and whether or not different signaling channels behave independently of each other. Our computational approach unifies seemingly disparate experimental observations and suggests specific changes in receptor trafficking patterns that can lead to phenotypes that favor tumor progression.

Computer Simulation↗
PubMed2005

Inferring the in vivo looping properties of DNA.

The free energy of looping DNA by proteins and protein complexes determines to what extent distal DNA sites can affect each other. We inferred its in vivo value through a combined computational-experimental approach for different lengths of the loop and found that, in addition to the intrinsic periodicity of the DNA double helix, the free energy has an oscillatory component of about half the helical period. Moreover, the oscillations have such an amplitude that the effects of regulatory molecules become strongly dependent on their precise DNA positioning and yet easily tunable by their cooperative interactions. These unexpected results can confer to the physical properties of DNA a more prominent role at shaping the properties of gene regulation than previously thought.

DNA↗
PubMed2005

DNA looping in gene regulation: from the assembly of macromolecular complexes to the control of transcriptional noise.

The formation of DNA loops by the binding of proteins and protein complexes at distal DNA sites plays a central role in many cellular processes, such as transcription, recombination and replication. Important thermodynamic concepts underlie the assembly of macromolecular complexes on looped DNA. The effects that this process has on the properties of gene regulation extend beyond the traditional view of DNA looping as a mechanism to increase the affinity of regulatory molecules for their cognate sites. Recent developments indicate that DNA looping can also lead to the suppression of cell-to-cell variability, the control of transcriptional noise, and the activation of cooperative interactions on demand.

Animals↗
PubMed2004

From molecular noise to behavioural variability in a single bacterium.

The chemotaxis network that governs the motion of Escherichia coli has long been studied to gain a general understanding of signal transduction. Although this pathway is composed of just a few components, it exhibits some essential characteristics of biological complexity, such as adaptation and response to environmental signals. In studying intracellular networks, most experiments and mathematical models have assumed that network properties can be inferred from population measurements. However, this approach masks underlying temporal fluctuations of intracellular signalling events. We have inferred fundamental properties of the chemotaxis network from a noise analysis of behavioural variations in individual bacteria. Here we show that certain properties established by population measurements, such as adapted states, are not conserved at the single-cell level: for timescales ranging from seconds to several minutes, the behaviour of non-stimulated cells exhibit temporal variations much larger than the expected statistical fluctuations. We find that the signalling network itself causes this noise and identify the molecular events that produce it. Small changes in the concentration of one key network component suppress temporal behavioural variability, suggesting that such variability is a selected property of this adaptive system.

Adaptation, Physiological↗