טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentSilvia Beha-Harpaz
SubjectPopulation Dynamics of Gene Regulatory Networks
DepartmentDepartment of Physics
Supervisor Full Professor Braun Erez


Abstract

The phenotype of a unicellular organism is determined by an integrated network of genes, proteins, and metabolites that participate in reciprocal regulatory relationships. A key challenge for biology is to understand the structure and the dynamics of the complex intercellular web of interactions that contribute to the structure and function of a living cell.

A first principle, modularity, is an oft-mentioned property of biological networks. Modularity is a fundamental design principle whereby components are partitioned according to common physical, regulatory, or functional properties.

While the modular structure of genetic regulatory networks is widely recognized, several recent works (based on mutations or stresses) made also clear that inter-modular interactions are of prime importance.

On the other hand, while most recent studies focus on static or short-term properties, measuring the long-term dynamics of these networks under controlled conditions is necessary for their complete characterization

The main goal of this work was to study the system-level gene regulation and inter-modular interactions by following the dynamics of adaptation of the global expression pattern, by switching cell populations between different (non-stressful) environments and monitoring their relaxation toward steady state.

The long term dynamics of physiological adaptation of yeast cells after the switch from galactose to glucose (two different carbon sources) was the focus of this work. Experiments were conducted for long time scales, several generations, while controlling the environment in continuous culture. This combination enabled to distinguish between transient responses and steady state.

DNA microarrays were used to analyze the adaptive dynamics of the genetic network. This technique allowed monitoring simultaneously the expression of thousands of genes during the adaptation providing a genome-wide view of the process.

It was found that while many genes vary their expression during transient periods, the expression patterns in the steady states are very similar to each other independently of the external conditions. The transient periods are characterized by global changes concerning many metabolic modules, but at the end of these periods when the steady state is achieved, the pattern of gene expression is not very different from the one before the change, even if the metabolic state is not the same. This result suggests that, while short-term dynamics are determined by specific modular responses, over long time scales inter-modular interactions take over and shape a robust steady state response of the regulatory system.