Descripción del proyecto
El papel de las modificaciones del ARN en el ciclo de vida de «Plasmodium falciparum»
«Plasmodium falciparum», el parásito que causa la malaria, presenta un ciclo de vida complejo y va alternando entre hospedadores humanos y mosquitos. Datos recientes subrayan la importancia de la regulación postranscripcional de la expresión génica en la supervivencia y la transmisión del parásito. Sin embargo, se desconocen en gran medida los mecanismos moleculares concretos. El proyecto financiado con fondos europeos PlasmoEpiRNA se centrará en la metilación de las adenosinas (m6A) en el ARNm e investigará el papel de esta modificación postranscripcional en las fases de desarrollo del parásito. Los resultados del proyecto desvelarán los determinantes que traducen estas modificaciones en el ARNm en distintas rutas biológicas y allanarán el camino hacia la identificación de nuevas dianas para combatir la malaria.
Objetivo
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.
Ámbito científico
Programa(s)
Régimen de financiación
ERC-STG - Starting GrantInstitución de acogida
75724 Paris
Francia