Gene regulation in response to graded hypoxia: The non-redundant roles of the oxygen sensors PHD and FIH in the HIF pathway

Frédéric Dayan (1, 2) , Marc Monticelli (2) , Jacques Pouysségur (1) , Elisabeth Pécou (2)

1 IBDC - Institut de signalisation, biologie du développement et cancer - Institute of Developmental Biology and Cancer
2 JAD - Laboratoire Jean Alexandre Dieudonné

Hif, being the master protein involved in adaptation to low p[O], plays a major role in many physiological and pathological phenomena: development, inflammation, ischemia and cancer. PHD and FIH are the two oxygen sensors that regulate the Hif pathway. Here we model the regulatory dynamics in an oxygen gradient by a system of differential equations. A part of the work consists in a qualitative analysis, driven independently of the values of the parameters, which explains the non-redundant functional roles of FIH and PH. In a second part, we use biological experiments to fit the model in a physiologically relevant context and run simulations. Simulation results are confronted with success to independent biological experiments. The combination of biological data and mathematical analysis stresses that FIH is a fine modulator determining whether a given gene should be induced in mildly or in strongly hypoxic areas. Moreover it gives access to other functional predictions that are not directly accessible by pure experiments, for instance the stoichiometry of prolyl-hydroxylation on Hif, and the switch-like properties of the system.

Mots clés: Gene expression; HIF; Mathematical model; Oxygen sensors; Switch-like behavior

Frédéric Dayan, Marc Monticelli, Jacques Pouysségur, Elisabeth Pécou. Gene regulation in response to graded hypoxia: The non-redundant roles of the oxygen sensors PHD and FIH in the HIF pathway. Journal of Theoretical Biology, 2009, 259 (2), pp.304. ⟨10.1016/j.jtbi.2009.03.009⟩. ⟨hal-00554587⟩