In collaboration with the Unit of Molecular Genetics of ARN viruses, the C3BI is organising a systems biology seminar with two scientists from Laszlo Barabasi’s laboratory :
Istvan Kovacs – A leap forward in biological link prediction
Biological function emerges from the complex interplay between molecules in our cells, comprising the human interactome. While interactions between proteins play a central role in the interactome, current maps are still missing the majority of these interactions. State-of-the-art network-based link prediction tools rely on the triadic closure principle, stating that proteins are likely to interact if they share many of their interaction partners, utilizing network paths of length l=2. We show that this principle is valid only for the small fraction of self-interacting proteins, while it fails completely for the rest of the network. Supported by both evolutionary and protein structural arguments, we identify missing protein interactions based on l=3 paths. Our top predictions validate as well experimentally as known protein-protein interactions, outperforming previous methods at least 2-3 fold. Our Length 3 Association Prediction (L3AP) approach provides a fundamental biological principle with a broad potential applicability, including also protein associations (i.e. co-complex membership) information, enabling us to better understand the emergence of biological function under both healthy and pathological conditions.
Marc Santolini – Perturbing the interactome: multi-omics and personalized methods for network medicine
Abstract: In this talk, I will describe several recently developed methods to study disease perturbations through the lens of network science. First I will present an investigation of the personalized gene expression responses when inducing hypertrophy and heart failure in 100+ strains of genetically distinct mice from the Hybrid Mouse Diversity Panel (HMDP). I will show that genes whose expression change significantly correlates with the severity of the disease are either up- or down-regulated across strains, and therefore missed by traditional population-wide analyses of differential gene expression. These uncovered personalised genes are enriched in human cardiac disease genes and form a dense co-regulated module strongly interacting with the cardiac hypertrophic signaling network in the human interactome, the set of molecular interactions in the cell. We validate our approach by showing that the knockdown of Hes1, predicted as a strong candidate, induces a dramatic reduction of hypertrophy by 80-90% in neonatal rat ventricular myocytes, demonstrating that individualized approaches are crucial to identify genes underlying complex diseases as well as to develop personalized therapies. Then, I will present a novel approach to identify the collective impact of miRNAs in disease. Instead of focusing on the magnitude of miRNA differential expression, here we address the secondary consequences for the interactome. We developed the Impact of Differential Expression Across Layers (IDEAL), a network-based algorithm to prioritize disease-relevant miRNAs based on the central role of their targets in the molecular interactome. This method was used in the context of asthmatic Th2 inflammation and identified five Th2-related miRNAs (mir27b, mir206, mir106b, mir203, and mir23b) whose antagonization led to a sharp reduction of the Th2 phenotype. This result offers novel approaches for therapeutic interventions. Finally, I will present evidence that one can accurately predict perturbation patterns from the topology of biological networks, even when lacking measurements on the kinetic parameters governing the dynamics of these interactions. Using 87 biochemical networks with experimentally measured kinetic parameters, we show that a knowledge of the network topology offers 65% to 80% accuracy in predicting the impact of perturbations. In other words, we can use the increasingly accurate topological models to approximate perturbation patterns, bypassing expensive kinetic constant measurement. These results open new avenues in modeling drug action, and in identifying drug targets relying on the human interactome only.
Bâtiment: Batiment Cantine
Adresse: Pasteur, Paris, France