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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.

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