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

• Published in: Nature microbiology Vol. 4; no. 12; pp. 2246 - 2259
• Main Authors: Baumgarten, Sebastian, Bryant, Jessica M., Sinha, Ameya, Reyser, Thibaud, Preiser, Peter R., Dedon, Peter C., Scherf, Artur
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.08.2019; Nature Publishing Group
• Subjects: 631/1647/296; 631/326/417/2550; 631/326/417/2551; 631/337/1645/2570; Biomedical and Life Sciences; CRISPR; Developmental stages; Erythrocytes; Gene expression; Gene regulation; Infectious Diseases; Life cycles; Life Sciences; Malaria; Mass spectroscopy; Medical Microbiology; Methyltransferase; Microbiology; Microbiology and Parasitology; mRNA stability; N6-methyladenosine; Parasites; Parasitology; Plasmodium falciparum; Post-transcription; Virology
• ISSN: 2058-5276; 2058-5276
• DOI: 10.1038/s41564-019-0521-7

Malaria pathogenesis results from the asexual replication of Plasmodium falciparum within human red blood cells, which relies on a precisely timed cascade of gene expression over a 48-h life cycle. Although substantial post-transcriptional regulation of this hardwired program has been observed, it remains unclear how these processes are mediated on a transcriptome-wide level. To this end, we identified mRNA modifications in the P. falciparum transcriptome and performed a comprehensive characterization of N 6 -methyladenosine (m 6 A) over the course of blood-stage development. Using mass spectrometry and m 6 A RNA sequencing, we demonstrate that m 6 A is highly developmentally regulated, exceeding m 6 A levels known in any other eukaryote. We characterize a distinct m 6 A writer complex and show that knockdown of the putative m 6 A methyltransferase, PfMT-A70, by CRISPR interference leads to increased levels of transcripts that normally contain m 6 A. In accordance, we find an inverse correlation between m 6 A methylation and mRNA stability or translational efficiency. We further identify two putative m 6 A-binding YTH proteins that are likely to be involved in the regulation of these processes across the parasite’s life cycle. Our data demonstrate unique features of an extensive m 6 A mRNA methylation programme in malaria parasites and reveal its crucial role in dynamically fine-tuning the transcriptional cascade of a unicellular eukaryote. An analysis of mRNA modifications in Plasmodium falciparum reveals m 6 A dynamics associated with parasite development within human red blood cells. m 6 A methylation is regulated by the methyltransferase PfMT-A70 and is linked to mRNA stability or translational efficiency.