Dissecting the role of PfAP2-G in malaria gametocytogenesis

Abstract

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.

CRISPR/Cas9-engineered inducible gametocyte producer lines as a novel tool for basic and applied research onPlasmodium falciparummalaria transmission stages

“…Gametocytes are the only forms of the malaria parasite that can secure human-to-human parasite transmission by the mosquito vector. While seminal research published in recent years provided major new insight into the regulatory mechanisms underlying sexual commitment and conversion 5,26-31,33-35,37,38,65 , our molecular understanding of gametocyte biology is still unsatisfactory. New experimental tools conducive to the detailed investigation of gametocytes and their transmission to mosquitoes will be crucial to close these knowledge gaps and to inform and support the development of transmission-blocking drugs and vaccines in a best possible way.…”

“…In asexual parasites, heterochromatin-dependent silencing of ap2-g prevents AP2-G expression 28,30-32 . In a small subset of trophozoites (NCC) or ring stages (SCC), however, the ap2-g locus gets activated by molecular mechanisms that are still largely unknown 27-31,33-35 . Gametocyte development 1 (GDV1), a nuclear protein essential for gametocytogenesis in P. falciparum 36 , plays a key role in the NCC process 34 .…”

“…Once expressed, PfAP2-G initiates a specific transcriptional programme that drives sexual conversion and subsequent gametocyte differentiation 5 . While the PfAP2-G-dependent transcriptional changes in sexually committed schizonts are minor, a more pronounced gene expression signature emerges in the sexually committed ring stage progeny, where several dozen genes are specifically induced or repressed compared to asexual ring stages 28,30,31,33,34,37,38 . Most of these upregulated genes are directly targeted by PfAP2-G 33 and encode proteins implicated in iRBC remodeling, while some others have expected roles in regulating gene expression during gametocyte maturation 28,30,31,33,34,37 .…”

“…Proteins linked to DNA replication and axoneme formation are enriched in males to prepare for the three rapid rounds of genome duplication and generation of eight motile microgametes during male gametogenesis 46-48 . Gametocytes also show increased expression of transcription factors and chromatin modifiers 28,30,33,39,44,45 , expanded subtelomeric heterochromatin domains 32,52 , distinct histone post-translational modification profiles 53 and altered three-dimensional chromosome organisation 52 . Furthermore, earlier studies investigating gametocyte morphology at the ultrastructural level described an intriguing nuclear dimorphism between female and male gametocytes 12,54 .…”

CRISPR/Cas9-engineered inducible gametocyte producer lines as a novel tool for basic and applied research on Plasmodium falciparum malaria transmission stages

“…While the PfAP2-G-dependent transcriptional changes in sexually committed schizonts are minor, a more pronounced gene expression signature emerges in the sexually committed ring stage progeny, where several dozen genes are speci cally induced or repressed compared to asexual ring stages 28,30,31,33,34,37,38 . Most of these upregulated genes are directly targeted by PfAP2-G 33 and encode proteins implicated in iRBC remodeling, while some others have expected roles in regulating gene expression during gametocyte maturation 28,30,31,33,34,37 .…”