Description du projet
L’instabilité génomique dans les cellules eucaryotes: un facteur d’adaptation?
Les Leishmania sont des parasites protozoaires transmis à l’homme et aux animaux par la piqûre de phlébotomes infectés, et sont à l’origine de diverses maladies. Contrairement à la plupart des cellules eucaryotes, les Leishmania peuvent augmenter l’expression de gènes spécifiques en modifiant le dosage des gènes par l’amplification de chromosomes entiers, de régions chromosomiques ou de gènes individuels. Financé par le Conseil européen de la recherche, le projet DECOLeishRN se propose d’étudier la manière dont les Leishmania utilisent cette instabilité du génome pour réguler leur adaptation. Les chercheurs se concentreront sur les mécanismes moléculaires qui peuvent filtrer les changements de dosage des gènes toxiques et bénéfiques, y compris les modifications de l’ARN guidées par les ARN non codants. Étant donné que l’instabilité génomique est à l’origine du développement du cancer, les résultats du projet s’étendent au-delà des Leishmania.
Objectif
Darwinian evolution plays a central yet poorly understood role in human disease. Iterations between genetic mutation and environmental selection drive cancer development, microbial infection and therapeutic failure, thus increasing human mortality. The molecular mechanisms that harness the deleterious effects of genome instability to generate beneficial phenotypes in these pathogenic systems are unknown. Here we investigate this important unsolved question in the protozoan parasite Leishmania that causes devastating human infections. In the absence of transcriptional regulation, these early-branching eukaryotes exploit genome instability to regulate expression by gene dosage. Leishmania thus represents an ideal system to investigate how genome instability drives fitness gain in fast evolving, eukaryotic cells, such as observed during cancer development. Synergizing our expertise in genomics, evolution, systems and RNA biology, we have recently made several breakthrough discoveries that link parasite fitness gain to epistatic interactions between co-amplifying genes of small, non-coding RNAs, which program epitranscriptomic and translational regulation. We hypothesize that these genome/RNome interactions generate the phenotypic landscape underlying Leishmania fitness gain. Our proposal investigates this ground-breaking concept through two Specific Aims that (i) combine experimental parasite differentiation and evolution in vitro and in vivo to reveal molecular mechanisms underlying Leishmania predictive adaptation and fitness gain, and (ii) investigate how RNA modification and non-coding RNAs contribute to adaptation by regulating mRNA stability and translational control. Our findings will be highly relevant to other fast growing, eukaryotic systems that rely on genome instability, such as cancer or fungal pathogens.
Champ scientifique
Mots‑clés
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thème(s)
Régime de financement
HORIZON-ERC-SYG - HORIZON ERC Synergy GrantsInstitution d’accueil
75724 Paris
France