Abstract
Scientific background and rationale : How biological systems respond and adapt to fast environmental changes is a challenging question. Over the last few years, epigenetic modifications have been considered as an interface between environmental factors and genetic information in living organisms, but remains to be fully demonstrated. Our proposal aims at evaluate the adaptive and evolutionary potential of non-genetic heritable mechanisms in experimentally controlled animal models. 2 – Description of the project methodology : The two groups involved in the project developed independently experimental paradigms in which phenotypic changes are under the control of non-genetic mechanisms. In two animals models, the mouse and the nematode C. elegans, external clues induce metabolic, physiologic or behavioural phenotypic modifications. Once induced, all modified phenotypes can be transmitted through out generation. As for most epigenetic heritable changes, only a few numbers of generations inherited the modified phenotypes. In the two models, inheritance pattern is not Mendelian: each individual from a generation switch from naive to modified (induction), express the modifications (inheritance), or switch from modified to naïve (reversion). In the two animal models, a central role for small non-coding RNA in mediating phenotypic changes has been identified. Such convergences suggest that common evolutionary conserved molecular mechanisms might be at work in different animals for different phenotypes in response to different external stimuli. Specific aims of the project: To identify what kind of epigenetic effectors are involved in producing the transient phenotypic modifications: In the mouse, one-cell embryo injection of non-coding RNA with sequence homology with the Sox-9 gene induces heritable giant phenotype. On the other hand, parental high-fat diet affects the body size of the progeny. In the worm, small RNAs are produced during the imprinting of odour stimuli at larval stages, modifying chemotaxis in adults. Small RNA can also transfer horizontally odour imprinting to naïve animals, suggesting they are responsible for the behavioural change. Combining biochemical, genetic, and RNA sequencing methods, we will identify odour-imprint RNA in odour imprinted worms, and sperm RNA in epigenetically transformed mice. We will look for epigenetic effectors in both models (RNAi pathways, DNA methylation, chromatin-modifier enzymes). To assess a possible stabilization of inheritance by repetitive induction: In the worm, maintaining the same odour stimuli in environment during five generations stably modify chemotaxis specifically to these odours in the population. Repetitive induction transforms a transient individual into a stable population adaptation. Then, we will search for genome modifications at specific loci or in whole genomes by comparing non-induced naïve and stably modified animals. Classical genetics will be used to study segregation pattern of the new innate chemotaxis behaviour. In the mouse models, we will repeat phenotypic change induction generation after generation, following phenotype evolution, gene expression, and phenotype inheritance as in the worm. Expected Results This project is primarily in fundamental research. Success or failure will have to be evaluated on the criteria of scientific publications. The role of non-coding RNA molecules in fast adaptative evolution is undoubtedly of general interest, and still very challenging in mouse In a more distant perspective, one may consider the possibility of identifying RNA molecules which might be used in the field of applied animal farming biotechnology.
France