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    Transcriptome-wide dynamics of extensive m6A mRNA methylation during Plasmodium falciparum blood-stage development 

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    Séminaire de l'Institut Cochin

    Lundi 12 novembre 2018 - 12h00 - Salle de conférence Rosalind Franklin, 2ème étage

     


    Sebastian Baumgarten

    Institut Pasteur, Paris

     

     invité par Julie Guignot

    Institut Cochin, 22 rue Méchain, 75014 Paris

     

    Résumé

    Malaria pathogenesis results from the massive asexual replication of Plasmodium falciparum within human red blood cells, a process that is based on a precisely timed periodic cascade of gene expression. However, the mechanism by which such a hardwired transcriptional program is fine-tuned at the protein expression level remains largely unknown. Chemical modifications on mRNA and especially the prevalent N6 methyladenosine (m6A) are emerging as a regulator of RNA homeostasis in higher eukaryotes. We determined the global mRNA modifications by mass-spectrometry in P. falciparum asexual blood stage development and identified m6A to be by far the most abundant and dynamically regulated modification. Surprisingly, it is present at up to 5-fold higher levels than in any other eukaryotic organism studied as yet, suggesting a prominent role for m6A in posttranscriptional regulation. We further demonstrated by parallel m6A immunoprecipitation and RNA sequencing that individual m6A sites are highly differentially methylated during the parasite’s development. Using CRISPR interference, we characterized the RNA methyltransferase PfMT-A70 as an evolutionarily conserved, integral member of the m6A writer complex. Disruption of m6A methylation leads to increased levels of transcripts that carry this modification in wild type parasites. Correspondingly, we found that m6A methylation inversely correlates with mRNA half-life as well as translational efficiencies. Collectively, this study demonstrates the regulatory potential of extensive m6A mRNA methylation in fine-tuning an inherently dynamic transcriptional program and adds a new ‘epitranscriptomic’ player of gene regulation in malaria parasites.

     

    Quelques publications

    • Droll, D., Wei. G., Guo, G.,Fan, Y., Baumgarten, S., Zhou, Y., Xiao, Y., Scherf, A., Zhang, Q (2018). Disruption of the RNA exosome reveals the hidden face of the malaria parasite transcriptome, RNA Biology
    • Baumgarten, S., Cziesielski, M.J., Thomas, L., Michell, C.T., Esherick, L.Y., Pringle, J.R., Aranda, M., Voolstra, C.R. (2018). Evidence for miRNA-mediated modulation of the host transcriptome in cnidarian–dinoflagellate symbiosis. Molecular Ecology, 27, 403-418
    • Zanghì, G., Vembar, S.S., Baumgarten, S., Ding, S., Guizetti, J., Bryant, J.M., Mattei, D., Jensen, A.T.R., Rénia, L., Goh, Y.S., et al. (2018). A specific PfEMP1 is expressed in P. falciparum sporozoites and plays a role in hepatocyte infection. Cell Reports, 22, 2951–2963.
    • Parkinson, J. E., Baumgarten, S., Michell, C. T., Baums, I. B., LaJeunesse, T. C. & Voolstra, C. R. (2016) Gene expression variation resolves species and individual strains among coral-associated dinoflagellates within the genus Symbiodinium. Genome Biology and Evolution, 8, 665-680
    • Baumgarten, S., Simakov, O., Esherick, L. Y., Liew, Y. J., Lehnert, E. M., Michell, C. T., Li, Y., Hambleton, E. A., Guse, A., Oates, M. E., Gough, J., Weis, V. M., Aranda, M., Pringle, J. R. & Voolstra, C. R. (2015) The genome of Aiptasia, a sea anemone model for coral symbiosis. Proceedings of the National Academy of Science of the USA, 112, 11893-11898.

     

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