Cells have to sense and to integrate signals, and they have to make decisions, when environmental conditions are changing. We are interested in their decision-making process including protein-DNA interactions defined by transcription factors and their targets around promoters as well as the impact of small RNA regulators which often interfere with target messenger RNAs modulating their translation and degradation.

Combining diverse expertise, we are an inter-disciplinary research team running experiments ranging from small-scale assays in a reaction tube to measurements of global gene expression in a bioreactor, well-defined ODE systems to large-scale data analysis.

Possible Master Student Projects

AG Axmann:
# A mathematical model for the KaiBC clock system in Prochlorococcus: Many organisms coordinate their activities according to daily cycles driven by an internal clock. In the blue-green alga Synechococcus, the core clock consists of just three proteins (KaiA, KaiB and KaiC) composing a post-translational oscillator (Brettschneider et al., 2010). In living cells, transcriptional feedback regulation is thought to be crucial for maintaining robust circadian rhythms. We have developed a mathematical model of interaction of two oscillators in which the KaiABC protein clock is coupled to rhythmic transcription and translation. This interaction mechanism is supposed to be adapted to a reduced version, the two-protein system found in another cyanobacterium, Prochlorococcus, harboring only KaiB and KaiC proteins. Finally, a mathematical model is aimed allowing us to evaluate experimental results and to propose a molecular mechanism responsible for the timekeeping mechanism in Prochlorococcus.

email: ilka.axmann (at) charite.de

AG Steuer / AG Lockau / AG Axmann:
Intro: We work on phototrophic cyanobacteria aiming to describe functional interactions at multiple hierarchies of cellular regulation. Specifically, the aim is to integrate metabolism, transcriptional regulation, the photosynthetic light reactions and the circadian clock into a coherent whole. Cyanobacteria have also attracted recent interest as a source of renewable biofuels, making use to synthesize valuable products directly from sunlight and CO2. All work should be carried out in close collaboration with the experimental groups at the HU Berlin.

Possible Topics:
[1] Metabolic regulation by asRNA [Axmann/Steuer, mainly computational]
The activity of metabolic networks (flux) is regulated at multiple levels. However, regulation by asRNA has as yet been neglected. Recent genome-wise transcription data show that a large number of enzyme have corresponding asRNA that are expressed at different times during the day. The aim of the thesis is to first map the known asRNA on the reconstructed metabolic network. Subsequently, the circadian expression should be analyzed. Part of the project is construct small-scale kinetic (possibly stochastic) models of asRNA to investigate the regulation at selected metabolic branchpoints. Our hypothesis is that asRNA establish temporal delays that allow to switch on metabolic pathway sequentially in time. Resources: transcription data for asRNA and enzymes, a detailed metabolic network reconstruction, existing models of asRNA by Legewie et al.


[2] Probabilistic modeling of the photosynthetic Calvin cycle [Steuer/Lockau, computational]
Kinetic modeling is often still significantly hampered by the lack of kinetic parameters. Therefore we developed an alternative approach, based on Monte-Carlo analysis, that allows to explore the dynamic properties of cellular pathways even when detailed information on parameters is lacking. This methodology should be applied to the photosynthetic Calcin cycle of cyanobacteria, based on existing models. The specific question to be investigated is the stability of the autocatalytic cycle upon depletion of intermediates, as for example, occurs in night/day transitions. Resources: Existing models of the Calvin cycle in plants, characterization of several key enzymes available, circadian expression of all enzymes available.

[3] Probabilistic modeling of the TCA cycle [Steuer/Lockau, computational]
Cyanobacteria possess an incomplete TCA cycle that differs from most other organisms. Our aim is therefore to construct a kinetic model of the cyanobacterial TCA cycle (Synechocystis 6803) to investigate its kinetic properties. The modeling procedure should use probabilistic methods to overcome the lack of kinetic parameters. Again, circadian regulation and the switch from photosynthetic metabolism to respiration should be investigated. Resources available: Existing models in higher plants, most metabolite concentrations can be determined experimentally in our labs, possibly also as part of a combined experimental/theoretical project.

[4] Optimality in the circadian clock [Steuer/Axmann, computational]
Only little is known about the selective advantage of a circadian clock to regulate cellular processes. Our aim is therefore to construct a minimal cell model that represents basic cellular processes and investigate the evolutionary advantage of a circadian clock by mathematical modeling. The project may employ in-silico evolution of cyanobacterial cells to study the emergence of circadian regulation.

email: steuer.ralf (at) googlemail.com

AG Westermark:
# Circadian control of the urea cycle
Metabolic modeling of the urea cycle in mouse hepatocytes. Integration of measured circadian oscillations of participating enzymes (Reddy et al. Current Biol 2006). Analysis and prediction of functional effects of this circadian rhythmicity.Application to cellular aging (Nakagawa and Guarente, Aging 2009).

# Glycolysis, gycogenesis, and gluconeogenesis in mouse liver.
Modeling and analysis of metabolic pathways that are incompatible, that is: not active at the same time (temporally compartmentalized). Analysis and prediction of function with particular emphasis on circadianly expressed enzymes, as estimated from publicly available microarray data. Application to cellular aging.

# AKT an mTOR signaling in mouse liver.
Analysis of circadian profiles of signaling proteins involved in AKT and mTOR signaling. Prediction of functional consequences possibly based on published models (G Wang, Phys Biol 2010). Application to cellular aging.

# Circadian clock and Per2 phosphorylation.
Theoretical investigation of some reaction motifs for the phosphorylation of the core mammalian circadian clock protein Per2. Prediction of functional consequences and comparison to data obtained e.g. in the Kramer lab, Charité.

email: p.westermark (at) biologie.hu-berlin.de