EPIGENESIS AND DYNAMIC SIMILARITY IN TWO REGULATORY NETWORKS IN PSEUDOMONAS AERUGINOSA Janine F. Guespin-Michel 1 , Gilles Bernot 2 , Jean Paul Comet 2 , Annabelle Mérieau 1 , Adrien Richard 2 , Christian Hulen 3 and Benoit Polack 4 1 Laboratoire de microbiologie du froid, EA 2123, Université de Rouen, F-76 821 Mt St Aignan, France. Email: janine.guespin@univ-rouen.fr (corresponding author). 2 LaMI, CNRS UMR 8042, Université d’Évry-Val-d’Essonne, Boulevard François Mitterrand, 91025 Evry Cedex, France. 3 Université de Cergy-Pontoise UFR sciences et techniques St Martin, 2 av A. Chauvin, BP 222, 95300 Pontoise, France. 4 GREPI EA 2938 Université Joseph Fourier Grenoble 1, Laboratoire d’Hématologie, CHU de Grenoble, BP 217, 38043 Grenoble cedex 9, France. ABSTRACT Mucoidy and cytotoxicity arise from two independent modifications of the phenotype of the bacterium Pseudomonas aeruginosa that contribute to the mortality and morbidity of cystic fibrosis. We show that, even though the transcriptional regulatory networks controlling both processes are quite different from a molecular or mechanistic point of view, they may be identical from a dynamic point of view: epigenesis may in both cases be the cause of the acquisition of these new phenotypes. This was highlighted by the identity of formal graphs modelling these networks. A mathematical framework based on formal methods from computer science was defined and implemented with a software environment. It allows an easy and rigorous validation and certification of these models and of the experimental methods that can be proposed to falsify or validate the underlying hypothesis. 1. INTRODUCTION The word epigenesis was first coined by Harvey in 1651, to describe the gradual formation of the different parts of an embryo. However, this word took on a new meaning when geneticists developed the notions of genotype and phenotype. Epigenetic modifications arise and can be transmitted from a cell to its progeny in the absence of genetic or environmental modifications. They may be triggered by an environmental signal but remain upon disappearance of this signal. Thus, several stable phenotypes may arise from the same genome in the same conditions. This is the biological equivalent of the physicist’s description of multiple steady states arising in non-linear dynamic systems. It has been shown in several instances that multistationarity is a good description of biological processes such as epigenesis (Guespin-Michel et al. , 2003), differentiation and memory (Delbrück, 1949; Demongeot, 1998; Casadesus and D’Ari, 2002). Thomas (1981) conjectured that a c 2004 Kluwer Academic Publishers. Printed in the Netherlands. Acta Biotheoretica 52: 379–390, 2004.