Effects of delay and noise in a negative-feedback genetic regulatory loop

by Prof. Matteo Palassini (Barcelona)

Wednesday 21 May 2008, 13:00 → 14:00 Europe/Stockholm

Nordita seminar room

Due to the small number of molecules involved in intracellular processes, stochastic fluctuations play an important role in gene regulation, and possible constructive effects of noise have received considerable attention. Another important, but often neglected, aspect of gene regulation are the long delays involved in the complex biochemical processes of transcription and translation. We study the interplay of intrinsic noise and delay in a model of the p53 core regulatory network. Recent experiments found pronounced coordinated oscillations in the concentrations of proteins p53 and Mdm2 in individual cells subjected to DNA damage. Oscillations have also been observed in other systems with negative feedback, such as the Hes1 and NF-$\kappa$B systems, and in circadian rhythms. Several mechanisms have been proposed to explain these findings, such as deterministic limit cycles (with or without delay) and noise-induced oscillations in the presence of a strong separation between fast and slow reactions. We consider a birth-and-death master equation model of the negative feedback loop between p53 and Mdm2, which does not assume a strong separation of reaction rates but takes into account the transcriptional and translational delay (at the price of analytical and computational complications due to the non-Markovian dynamics). Via exact stochastic simulations, we find pronounced noise-induced oscillations in a wide region of parameters for which there are no sustained oscillations in the deterministic limit, in qualitative agreement with the experimental results. We speculate that this may be a generic mechanism for oscillations in gene regulatory systems.