In the malaria parasite Plasmodium falciparum, the switch from asexual multiplication to sexual differentiation into gametocytes is essential for transmission to mosquitos. The transcription factor PfAP2-G is a key determinant of sexual commitment that orchestrates this crucial cell fate decision. Here we identify the direct targets of PfAP2-G and demonstrate that it dynamically binds hundreds of sites across the genome. We find that PfAP2-G is a transcriptional activator of early gametocyte genes, and identify differences in PfAP2-G occupancy between gametocytes derived via next-cycle and same-cycle conversion. Our data implicate PfAP2-G not only as a transcriptional activator of gametocyte genes, but also as a potential regulator of genes important for red blood cell invasion. We also find that regulation by PfAP2-G requires interaction with a second transcription factor, PfAP2-I. These results clarify the functional role of PfAP2-G during sexual commitment and early gametocytogenesis.
In the malaria parasite Plasmodium falciparum, the switch from asexual multiplication to sexual differentiation into gametocytes is essential for transmission to mosquitos. One of the key determinants of sexual commitment is the transcription factor PfAP2-G, which has been proposed to orchestrate this crucial cell fate decision by driving expression of gametocyte genes.We show conclusively that PfAP2-G is a transcriptional activator of gametocyte genes and identify the earliest known markers expressed during commitment. Remarkably, we also find that in sexually committed cells, PfAP2-G is associated with the promoters of genes important for red blood cell invasion and activates them through its interactions with a second transcription factor. We thus demonstrate an intriguing transcriptional link between the apparently opposing processes of red blood cell invasion and gametocytogenesis that is coordinated by the master regulator PfAP2-G. This finding has important implications for the development of new antimalarial drugs that block the invasion of red blood cells by sexually committed cells, thereby preventing parasite transmission.
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