Isambert

RNA Dynamics and Biomolecular Systems

Hervé Isambert
Scientific keywords: Biomolecular networks, Genome and network evolution, RNA folding simulations, RNA nanostructures, Whole genome duplication and Cancer

Our research concerns the properties and evolution of biomolecular networks at different scales, from their simple local structures to their more complex global organization.

Evolution of large biomolecular networks

We are interested in the properties of large biomolecular networks and their evolution due to genomic duplication-divergence processes at the level of individual genes and whole genome duplications (WGD), which occurred repeatedly in the course of eukaryote evolution (Fig.1).

Our theoretical approach relies on a general duplication-divergence model, based on the necessary deletions of some functional interactions arising from stochastic duplications. We have shown that duplication-divergence processes bring not only genetic novelty but also evolutionary constraints that restrict by construction the emerging properties of biomolecular networks (Evlampiev et al. PNAS 2008, Stein et al. PRE 2011). In particular, we could demonstrate that networks with conserved genes, which are networks of prime biological relevance, are also necessary scale-free by construction. We are also interested in the evolution of transcription networks and study the regulatory conflicts that arise through duplication of trancription factors and autoregulators (Cosentino Lagomarsino et al. PNAS 2007).

More recently, we have been studying the evolutionary constraints on signaling networks implicated in cancer (Fig.2). We investigate the evidences that the emerging properties of these signaling pathways might actually reflect their susceptibility to oncogenic mutations, that are often related to functional autoinhibition constraints of many oncogenes. We have found, in particular, that “dangerous” gene families implicated in cancer have been greatly expanded through two rounds of whole genome duplication (WGD) (Fig. 2) in early vertebrates (Singh et al. Cell Rep. 2012). These findings highlight the importance of WGD-induced nonadaptive selection for the emergence of vertebrate complexity, while rationalizing, from an evolutionary perspective, the expansion of gene families frequently implicated in genetic disorders and cancers.
 
RNA regulatory networks and RNA nanostructures.

We have also studied the properties of small regulatory circuits primary based on RNAs and their interactions. In particular, we have used synthetic biology approaches coupled to advanced RNA dynamics simulations (http://kinefold.curie.fr) to design efficient RNA-based repressor and activator modules. These modules control RNA transcription “on the fly” through simple RNA-RNA antisense interactions (Dawid et al. Phys Biol 2009, Xayaphoummine et al. NAR 2007). We also discovered that DsrA, a small bacterial RNA of Escherichia coli could self-assemble, like many proteins do, to form long filaments and larger physical networks (Fig3) (Cayrol et al. JACS 2009). This finding further extends the already great versality of natural RNA functions.

Whole Genome Duplication in eukaryote evolution.

Figure 1: Whole Genome Duplication in eukaryote evolution.

Figure 2: Ras-Ral pathways expansion through Whole genome duplication in vertebrates.

Figure 2: Ras-Ral pathways expansion through Whole genome duplication in vertebrates.

Figure 3: Novel nanostructures made of DsrA ncRNA from E.coli.

Figure 3: Novel nanostructures made of DsrA ncRNA from E.coli.