Inria / Raweb 2004
Project-Team: MODBIO

Search in Activity Report, year 2004:


Project-Team : modbio

Section: New Results

Keywords: Modeling, hybrid system, constraint programming, alternative splicing, HIV-1.

Modeling of alternative splicing regulation

Participants: Alexander Bockmayr, Arnaud Courtois, Damien Eveillard, Myriam Vezain.

Alternative splicing is a key process in post-transcriptional regulation, by which several kinds of mature RNA can be obtained from the same premessenger RNA. The resulting combinatorial complexity contributes to biological diversity, especially in the case of the human immunodefficiency virus HIV-1. In collaboration with the UMR 7567 MAEM in Nancy, we have developed different formal models of the alternative splicing regulation in HIV-1 [14].

Despite its importance for the HIV-1 life cycle, the consequences of alternative splicing regulation have not yet been well studied experimentally. In order to overcome this difficulty, we propose an integrative model based on a hybrid automaton with default reasoning [17][11][23]. This hybrid automaton integrates continuous models of the local regulation at the splicing sites A3 and A7 together with assumptions on the sites A4 and A5 into a generic multi-site model. Using this approach, we may study the impact of the regulation at one activator site on the production of the HIV-1 proteins characteristic for the late phase of the disease. As an example, we analysed the impact of increasing the concentration of the splicing inhibitory protein hnRNPA1. Based on biological queries and a model checking approach, our model can be validated in a qualitative way. In addition, we may generate hypotheses for future experimental work.

The multi-site model of alternative splicing regulation has also been integrated into a model of the HIV-1 life cycle [39], see [11][23]. We are currently performing a theoretical analysis of this new model in order to study the global effect of alternative splicing regulation at the level of the HIV-1 life cycle.