A transcriptional switch underlies commitment to sexual development in malaria parasites

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Abstract
The DNA-binding protein PfAP2-G is found to be a master regulator of sexual development in the malaria parasite; this protein appears to regulate early gametocytogenesis and is epigenetically silenced in the majority of blood-stage parasites. For malaria parasites to be transmitted to the mosquito vector they must undergo sexual development and produce gametocytes. The molecular mechanisms underlying the commitment to gametocyte development have been unclear. Two complementary manuscripts now show that AP2-G, a member of the apicomplexan AP2 family of transcription factors, is a master regulator of sexual development in the malaria parasite, acting as a developmental switch by triggering the transcription of early gametocyte genes. Abhinav Sinha et al. worked with the rodent malaria parasite Plasmodium berghei, and Björn Kafsack et al. with the human pathogen P. falciparum. AP2-G activity in human infectious malaria parasites could be a potential target for antimalarials designed to interfere with gametocyte formation. The life cycles of many parasites involve transitions between disparate host species, requiring these parasites to go through multiple developmental stages adapted to each of these specialized niches. Transmission of malaria parasites (Plasmodium spp.) from humans to the mosquito vector requires differentiation from asexual stages replicating within red blood cells into non-dividing male and female gametocytes. Although gametocytes were first described in 1880, our understanding of the molecular mechanisms involved in commitment to gametocyte formation is extremely limited, and disrupting this critical developmental transition remains a long-standing goal1. Here we show that expression levels of the DNA-binding protein PfAP2-G correlate strongly with levels of gametocyte formation. Using independent forward and reverse genetics approaches, we demonstrate that PfAP2-G function is essential for parasite sexual differentiation. By combining genome-wide PfAP2-G cognate motif occurrence with global transcriptional changes resulting from PfAP2-G ablation, we identify early gametocyte genes as probable targets of PfAP2-G and show that their regulation by PfAP2-G is critical for their wild-type level expression. In the asexual blood-stage parasites pfap2-g appears to be among a set of epigenetically silenced loci2,3 prone to spontaneous activation4. Stochastic activation presents a simple mechanism for a low baseline of gametocyte production. Overall, these findings identify PfAP2-G as a master regulator of sexual-stage development in malaria parasites and mark the first discovery of a transcriptional switch controlling a differentiation decision in protozoan parasites.

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