The PfAP2‐G2 transcription factor is a critical regulator of gametocyte maturation

Abstract

Differentiation from asexual blood stages to mature sexual gametocytes is required for the transmission of malaria parasites. Here, we report that the ApiAP2 transcription factor, PfAP2‐G2 (PF3D7_1408200) plays a critical role in the maturation of Plasmodium falciparum gametocytes. PfAP2‐G2 binds to the promoters of a wide array of genes that are expressed at many stages of the parasite life cycle. Interestingly, we also find binding of PfAP2‐G2 within the gene body of almost 3,000 genes, which strongly correlates with the location of H3K36me3 and several other histone modifications as well as Heterochromatin Protein 1 (HP1), suggesting that occupancy of PfAP2‐G2 in gene bodies may serve as an alternative regulatory mechanism. Disruption of pfap2‐g2 does not impact asexual development, but the majority of sexual parasites are unable to mature beyond stage III gametocytes. The absence of pfap2‐g2 leads to overexpression of 28% of the genes bound by PfAP2‐G2 and none of the PfAP2‐G2 bound genes are downregulated, suggesting that it is a repressor. We also find that PfAP2‐G2 interacts with chromatin remodeling proteins, a microrchidia (MORC) protein, and another ApiAP2 protein (PF3D7_1139300). Overall our data demonstrate that PfAP2‐G2 establishes an essential gametocyte maturation program in association with other chromatin‐related proteins.

The private life of malaria parasites: Strategies for sexual reproduction

“…Or perhaps asexual cells sense and respond to environmental/state cues as individuals but in a probabilistic manner, such that on average across the cohort, the best trait values for sex ratio and conversion rates manifest. Both of these scenarios are compatible with recent suggestions that only a sub-population of asexuals within each IDC have the potential to leave the asexual cycle [ 1 , 2 , 8 , 10 , 71 , 100 , 101 ]. Such a strategy may be a safety catch, preventing all asexuals converting and/or all gametocytes differentiating into the same sex.…”

“…The involvement of AP2-G as a master regulator of commitment and the regulation of AP2-G expression through silencing by H3K3me3 and HP1, occurs across species [ 3 , 4 , [6] , [7] , [8] , [9] , 11 , 103 ]. However, multiple studies reveal gametocyte-specific genes are expressed before AP2-G, suggesting that there is a pre-commitment program that may prepare (potentially a subset of) asexuals for future commitment [ 1 , 2 , 8 , 10 , 71 , 100 , 101 ]. Without AP2-G, gametocyte transcripts may not be stabilised and commitment aborted [ 1 , 101 ].…”

“…Thus, AP2-G expression within an IDC provides a readout for conversion when related to the number of asexuals in that cohort, but may not be instrumental in determining what the conversion rate should be. Furthermore, the timing of sex allocation is unclear, and it may occur prior to AP2-G mediated processes, and thus may also be part of a program of molecular preparedness (pre-commitment) that takes place before the irreversible AP2-G checkpoint [ 1 , 2 , 8 , 10 , 71 , 100 , 101 ] ( Fig. 4 ).…”

Prion‐like proteins: from computational approaches to proteome‐wide analysis

“…Between the prion-like constituent functional domains, the most enriched ones were those related to nucleotide-binding, including the ubiquitous RRM, but also domains not detected in other organisms such as the ApiAP2 domain. Indeed, [118], playing crucial roles in gametocyte maturation [119], organ infection [120] and the development of host immunity [121]. Thus, the analysis uncovered the association of putative PrLDs with essential functions connected with Plasmodium life cycle regulation and its adaptation to the host.…”

A dynamic and combinatorial histone code drives malaria parasite asexual and sexual development

“…To further investigate the epigenetic complexes associated with H3K18ac and H3K23ac, protein-protein interaction data were used to assemble a proposed reader complex for these PTMs in mature stage gametocytes, associated with AP2-G2 (Fig 6C) (Hoeijmakers et al, 2019;LaCount et al, 2005;Singh et al, 2020) (Appendix 3).…”