Description du projet
Le rôle des modifications de l’ARN dans le cycle de vie du Plasmodium
Plasmodium falciparum, le parasite responsable du paludisme, a un cycle de vie complexe, changeant constamment d’hôte, qu’il s’agisse d’humains ou de moustiques. De nouvelles données soulignent l’importance de la régulation post-transcriptionnelle de l’expression génétique dans la survie et la transmission du parasite. Toutefois, les mécanismes moléculaires précis restent largement méconnus. Le projet PlasmoEpiRNA, financé par l’UE, s’intéressera à la méthylation de l’ARNm des adénosines (m6A) et examinera le rôle de cette modification post-transcriptionnelle sur les étapes du développement du parasite. Les résultats du projet mettront en lumière les facteurs déterminants qui permettent de traduire ces modifications de l’ARNm en voies biologiques distinctes et faciliteront l’identification de nouvelles cibles pour lutter contre le paludisme.
Objectif
Post-transcriptional regulation in malaria parasites is key to the progression through different developmental stages of the complex life cycle within the human and mosquito host. This includes the asexual proliferation within human red blood cells that is responsible for all clinical symptoms of the disease and the preparation for the environmental changes accompanying transmission from host to vector and vice versa. Although the process that controls the destiny of mRNA are of critical importance to parasite survival and transmission, the molecular mechanisms orchestrating post-transcriptional regulation on a transcriptome-wide level remain largely unknown. We recently identified extensive methylation of adenosines (m6A) at internal mRNA positions as a new layer of post-transcriptional regulation of gene expression in Plasmodium falciparum. With m6A, the parasite dynamically modulates its transcriptome through selective mRNA degradation and/or translational repression of modified transcripts during blood-stage development. This new epitranscriptomic layer provides a previously missing link between the transcriptional program and the observed post-transcriptional events throughout P. falciparum development. The proposed project aims to elucidate how m6A mediates different outcomes of mRNA at key developmental stages of the parasite life cycle. We will 1) characterize m6A-binding proteins and elucidate how different m6A ‘readers’ translate this mRNA modification into distinct biological pathways (i.e. degradation, repression) during blood-stage development and 2) investigate how m6A and its specific reader proteins designate mRNAs to facilitate transient quiescence in transmission stages (i.e. gametocytes and sporozoites) to ‘prime’ the transcriptome for new host/vector environments. Overall, exploring the epitranscriptome of this parasite will reveal novel principles and molecular determinants of post-transcriptional control that can be targeted to combat malaria.
Champ scientifique
Programme(s)
Thème(s)
Régime de financement
ERC-STG - Starting GrantInstitution d’accueil
75724 Paris
France