Madalena Chaves - UCA, Inria Sophia Antipolis, team Biocore - Keywords: modeling and coupling biological oscillators

Madalena Chaves - UCA, Inria Sophia Antipolis, team Biocore - Keywords: modeling and coupling biological oscillators

Contribution title: A mathematical control viewpoint on the interactions between mammalian cell cycle and circadian clock

Mammalian cells have evolved highly sophisticated intracellular communication pathways to enable their development and growth, under multiple environmental stresses and stimulus (nutrition availability, temperature or light changes, etc.). Two major cyclic processes are at the basis of cell development: the cell cycle and the circadian clock, both of which have been separately studied from many diverse points of view. However, the links between the cell cycle and circadian clock oscillators are still not fully understood and many questions remain on the coupling between these two modules.

From a mechanistic point of view, the coupling between cell cycle and circadian clock can be represented as a control theoretic problem, by a system with inputs and outputs and its controller. In many organisms, there is evidence supporting regulation of the cell cycle by the circadian clock, but it was only recently that research focused on the two-way feedback coupling between these two modules.

Directly studying the mechanisms of interaction between these two cellular modules is a most challenging task, due to the intrinsic complexity of the networks, the difficulty in isolating specific events in a “natural” cell, and the demanding experimental techniques. In our project, we are developing reduced mathematical models of both mammalian oscillators that recover all their basic properties. The objective is to use these models to design simple circuits that will be synthetically assembled from molecular components in a cell (DNA sequences, proteins). In a first step, the reduced models have been calibrated and validated against biological data, and they have been used to analyse the coupling possibilities between the two circuits. We will summarize our current results and conclusions on mathematical modeling, coupling, and analysis of the two oscillatory systems.

Some references:
S. Almeida, M. Chaves, F. Delaunay, and C. Feillet. A comprehensive reduced model of the mammalian cell cycle. Proc. 20th IFAC World Congress, Toulouse, France, Jul. 2017.
C. Feillet, P. Krusche, F. Tamanini, R.C. Janssens, M.J. Downey, P. Martin, M. Teboul, S. Saito, F.A. Levi, T. Bretschneider, G.T.J. van der Horst, F. Delaunay, and D.A. Rand. Phase locking and multiple oscillating attractors for the coupled mammalian clock and cell cycle. PNAS, 111(27):9828-9833, 2014.