RT Journal Article SR Electronic T1 Hierarchical transcriptional control regulates Plasmodium falciparum sexual differentiation JF bioRxiv FD Cold Spring Harbor Laboratory SP 633222 DO 10.1101/633222 A1 Riëtte van Biljon A1 Roelof van Wyk A1 Heather J. Painter A1 Lindsey Orchard A1 Janette Reader A1 Jandeli Niemand A1 Manuel Llinás A1 Lyn-Marie Birkholtz YR 2019 UL http://biorxiv.org/content/early/2019/05/09/633222.abstract AB Although malaria is characterized by cyclic waves of infection by asexual parasites, only sexual gametocyte forms of the malaria parasite can be transmitted between the infected human and the mosquito host. Here we provide a high-resolution transcriptome of P. falciparum as it commits to and develops through gametocytogenesis and prepares for transmission to the mosquito vector. As anticipated, the gametocyte-associated transcriptome is significantly different from that of the asexual blood cycle, and a dynamic shift in gene expression characterizes early, intermediate and late-stage gametocyte development. Moreover, we show a differential timing in the expression of sex-specific transcripts and we highlight early male and female gametocyte markers for functional evaluation. The striking temporal transcript abundance profiles suggest that strict transcriptional control underlies the 10-day gametocyte developmental program in P. falciparum. We identify putative regulators of transcriptional dynamics, including epigenetic mechanisms driving active repression of processes typically associated with proliferation and ApiAP2 transcription factors expressed during gametocyte maturation. The gametocyte transcriptome serves as the blueprint for sexual differentiation at the mRNA transcript level and will be a rich resource for future functional studies on this critical stage of Plasmodium development, as the intraerythrocytic transcriptome has been for our understanding of the 48-hour asexual cycle.Author Summary The ability of the malaria parasite Plasmodium falciparum to smoothly transition between the human and the female mosquito hosts is one of the hallmarks of the pathogenicity of the disease. Only sexually dimorphic, mature gametocyte stages of the parasite life cycle can complete the human-to-mosquito transmission task. However, we do not clearly understand how these gametocytes develop and mature. Here, we report the highest resolution investigation of the gametocyte’s transcriptional profile during development and differentiation. This information sheds light on several possible regulators that mediate parasite maturation into transmission-competent stage V gametocytes. We find that 15% of the parasite’s transcripts are developmentally regulated within three distinct phases of sexual development, each corresponding to essential biological events allowing for regulated and staged differentiation. Our study lays the foundation for future projects aiming to therapeutically target these transmissible stages and comprises an invaluable resource for the study of malaria parasite pathogenesis.