RT Journal Article
SR Electronic
T1 Model checking to assess T-helper cell plasticity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 012641
DO 10.1101/012641
A1 Wassim Abou-Jaoudé
A1 Pedro T. Monteiro
A1 Aurélien Naldi
A1 Maximilien Grandclaudon
A1 Vassili Soumelis
A1 Claudine Chaouiya
A1 Denis Thieffry
YR 2014
UL http://biorxiv.org/content/early/2014/12/12/012641.abstract
AB Computational modeling constitutes a crucial step towards the functional understanding of complex cellular networks. In particular, logical modeling has proven suitable for the dynamical analysis of large signaling and transcriptional regulatory networks. In this context, signaling input components are generally meant to convey external stimuli, or environmental cues. In response to such external signals, cells acquire specific gene expression patterns modeled in terms of attractors (e.g. stable states). The capacity for cells to alter or reprogram their differentiated states upon changes in environmental conditions is referred to as cell plasticity.In this article, we present a multivalued logical framework along with computational methods recently developed to efficiently analyze large models. We mainly focus on a symbolic model checking approach to investigate switches between attractors subsequent to changes of input conditions.As a case study, we consider the cellular network regulating the differentiation of T-helper cells, which orchestrate many physiological and pathological immune responses. To account for novel cellular subtypes, we present an extended version of a published model of T-helper cell differentiation. We then use symbolic model checking to analyze reachability properties between T-helper subtypes upon changes of environmental cues. This allows for the construction of a synthetic view of T-helper cell plasticity in terms of a graph connecting subtypes with arcs labeled by input conditions. Finally, we explore novel strategies enabling specific T-helper cell polarizing or reprograming events.