Project description
The role of RNA modifications in the Plasmodium life cycle
Plasmodium falciparum, the causative parasite of malaria, undergoes a complex life cycle, switching between the human and mosquito hosts. Emerging evidence underscores the importance of post-transcriptional regulation of gene expression in parasite survival and transmission. However, the precise molecular mechanisms remain largely unknown. The EU-funded PlasmoEpiRNA project will focus on mRNA methylation of adenosines (m6A) and investigate the role of this post-transcriptional modification on the parasite developmental stages. Project results will unveil the determinants that translate these mRNA modifications into distinct biological pathways and pave the way towards the identification of novel targets to combat malaria.
Objective
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.
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Funding Scheme
ERC-STG - Starting GrantHost institution
75724 Paris
France