Alexander Hunziker – Niels Bohr Institute - University of Copenhagen

Alexander Hunziker

Title: Sense & Sensitivity - Regulation of Genes in Good and Bad Times

A thesis submitted august 2, 2010 for the degree of Doctor of Philosophy and defended september 17, 2010.

The PhD School of Science
Faculty of Science
Niels Bohr Institute
Center for Models of Life
University of Copenhagen

Mogens Høgh Jensen
Szabolcs Semsey
Sandeep Krishna

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Sense & Sensitivity - Regulation of Genes
in Good and Bad Times

This PhD thesis describes three research projects which, along different lines, looked into how cells integrate external signals. Some projects being pure modelling work and others involving laboratory work, this thesis is at the interface of theory and experiments.

In the first project, we engineered E. coli with custom made promoters with the aim of getting the cells to integrate two external signals according to certain logics belonging to the class of Boolean functions. We wanted to find out how diverse a set of logics we could obtain by exploiting only mechanisms of transcription regulation. We were able to implement 12 of the 16 Boolean functions and conclude that transcription regulation provides cells with a very 􀄘exible toolbox to adapt to new environmental conditions.

The second project looks at a central part of many mammalian cells' stress response system, the p53 pathway. Even though all cell stresses are integrated through the same central node, the p53 protein, the pathway can trigger responses which are very diverse and stress-specific. We argue that it is the particular design of the p53-MDM2 feedback loop, with a negative feedback featuring a relatively slow transactivation leg and a fast inhibition leg, which makes this possible.

Finally, the third project looks at the timing of gene expression in E. coli's galactose utilisation system, as a culture of cells grow to stationary phase on a limited galactose pool. It is assumed that the structure of gene regulatory networks in an organism evolves to deal with the kind of environmental situations it most frequently encounters. By observing the dynamics of how the culture uses up the given sugar pool, we deduce that E. coli evolved to live in environments which feature unpredictable food availability, as opposed to so-called feast and famine cycles.

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