The large-scale logico-chemical structure of a transcriptional regulation network

Methods of modeling cellular regulatory networks as diverse as differential equations and Boolean networks co-exist, however, without any closer correspondence to each other. With the example system of the fission yeast cell cycle control network, we here set the two approaches in relation to each other. We find that the Boolean network can be formulated as a specific coarse-grained limit of the more detailed differential network model for this system. This lays the mathemati...

Genetic regulatory networks enable cells to respond to the changes in internal and external conditions by dynamically coordinating their gene expression profiles. Our ability to make quantitative measurements in these biochemical circuits has deepened our understanding of what kinds of computations genetic regulatory networks can perform and with what reliability. These advances have motivated researchers to look for connections between the architecture and function of geneti...

Motivation: Many problems in biomedicine and other areas of the life sciences can be characterized as control problems, with the goal of finding strategies to change a disease or otherwise undesirable state of a biological system into another, more desirable, state through an intervention, such as a drug or other therapeutic treatment. The identification of such strategies is typically based on a mathematical model of the process to be altered through targeted control inputs....

Motivation: Cell-biological processes are regulated through a complex network of interactions between genes and their products. The processes, their activating conditions, and the associated transcriptional responses are often unknown. Organism-wide modeling of network activation can reveal unique and shared mechanisms between physiological conditions, and potentially as yet unknown processes. We introduce a novel approach for organism-wide discovery and analysis of transcrip...

Recent developments in Omics-technologies revolutionized the investigation of biology by producing molecular data in multiple dimensions and scale. This breakthrough in biology raises the crucial issue of their interpretation based on modelling. In this undertaking, network provides a suitable framework for modelling the interactions between molecules. Basically a Biological network is composed of nodes referring to the components such as genes or proteins, and the edges/arcs...

The engineered control of cellular function through the design of synthetic genetic networks is becoming plausible. Here we show how a naturally occurring network can be used as a parts list for artificial network design, and how model formulation leads to computational and analytical approaches relevant to nonlinear dynamics and statistical physics.

Recent experimental advances in biology allow researchers to obtain gene expression profiles at single-cell resolution over hundreds, or even thousands of cells at once. These single-cell measurements provide snapshots of the states of the cells that make up a tissue, instead of the population-level averages provided by conventional high-throughput experiments. This new data therefore provides an exciting opportunity for computational modelling. In this paper we introduce the...

Computational models of biological processes provide one of the most powerful methods for a detailed analysis of the mechanisms that drive the behavior of complex systems. Logic-based modeling has enhanced our understanding and interpretation of those systems. Defining rules that determine how the output activity of biological entities is regulated by their respective inputs has proven to be challenging, due to increasingly larger models and the presence of noise in data, all...

In this paper, we analyse large random Boolean networks in terms of a constraint satisfaction problem. We first develop an algorithmic scheme which allows to prune simple logical cascades and under-determined variables, returning thereby the computational core of the network. Second we apply the cavity method to analyse number and organisation of fixed points. We find in particular a phase transition between an easy and a complex regulatory phase, the latter one being charact...

This Thesis presents research at the boundary between Statistical Physics and Biology. First, we have devised a class of Boolean constraint satisfaction problems (CSP) whose solutions describe the feasible operational states of a chemical reaction network. After developing statistical mechanics techniques to generate solutions and studying the properties of the solution space for both ensembles and individual instances of random reaction networks, we have applied this framewo...