Biomedical subjects

Paul François

Publications and source records attributed to Paul François.

3 recordsLinked to original sources

PubMed2005

Core genetic module: the mixed feedback loop.

The so-called mixed feedback loop (MFL) is a small two-gene network where protein A regulates the transcription of protein B and the two proteins form a heterodimer. It has been found to be statistically over-represented in statistical analyses of gene and protein interaction databases and to lie at the core of several computer-generated genetic networks. Here, we propose and mathematically study a model of the MFL and show that, by itself, it can serve both as a bistable switch and as a clock (an oscillator) depending on kinetic parameters. The MFL phase diagram as well as a detailed description of the nonlinear oscillation regime are presented and some biological examples are discussed. The results emphasize the role of protein interactions in the function of genetic modules and the usefulness of modeling RNA dynamics explicitly.

Cell Physiological Phenomena↗

PubMed2005

A model for the Neurospora circadian clock.

Circadian clocks are important biological oscillators that generally involve two feedback loops. Here, we propose a new model for the Neurospora crassa circadian clock. First, we model its main negative feedback loop, including only experimentally well-documented reactions, the transcriptional activation of frequency (frq) by the white-collar complex (WCC), and the post-transcriptional dimerization of FRQ with WCC. This main loop is sufficient for oscillations and a similar one lies at the core of almost all known circadian clocks. Second, the model is refined to include the less characterized enhancement of white-collar 1 (WC-1) protein synthesis by FRQ, the positive second feedback loop. Numerical testing of different hypotheses led us to propose that the synthesis of WC-1 is enhanced by FRQ monomers and repressed by FRQ dimers. We demonstrate that this second loop contributes significantly to the robustness of the oscillator period against parameter variation. A phase response curve to light pulses is also computed and agrees well with experiments. On a general level, our results show that explicit time delays are not required for sustained oscillations but that it is crucial to take into account mRNA dynamics and protein-protein interactions.

Biological Clocks↗

PubMed2004

Design of genetic networks with specified functions by evolution in silico.

Recent studies have provided insights into the modular structure of genetic regulatory networks and emphasized the interest of quantitative functional descriptions. Here, to provide a priori knowledge of the structure of functional modules, we describe an evolutionary procedure in silico that creates small gene networks performing basic tasks. We used it to create networks functioning as bistable switches or oscillators. The obtained circuits provide a variety of functional designs, demonstrate the crucial role of posttranscriptional interactions, and highlight design principles also found in known biological networks. The procedure should prove helpful as a way to understand and create small functional modules with diverse functions as well as to analyze large networks.

Algorithms↗