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

Abstract

Differentiation from asexual blood stages to sexual gametocytes is required for transmission of malaria parasites from the human to the mosquito host. Preventing gametocyte commitment and development would block parasite transmission, but the underlying molecular mechanisms behind these processes remain poorly understood. 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 3000 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, parasite multiplication rate, or commitment to sexual 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 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 is an important transcription factor that establishes an essential gametocyte maturation program in association with other chromatin-related proteins.

H3K36 Methylation Reprograms Gene Expression to Drive Early Gametocyte Development in Plasmodium Falciparum

“…4c). This suggests an interaction between these two regulatory mechanisms and supports previous descriptions of AP2-G2 as a transcriptional repressor (59). The number of H3K36me2&3-enriched sites is somewhat reduced in the post-stage II gametocytes (54%) as expected given the residual hPTM occupancy patterns in these later gametocyte stages that are reminiscent of H3K36me2/3 enrichment in the stage II gametocytes.…”

“…We also assessed the H3K36me2/3 enrichment in our gametocyte populations at sites occupied by a second ApiAP2 transcription factor, AP2-G2 (PF3D7_1408200), during intermediate gametocyte development (59). AP2-G2 is not essential for asexual parasite proliferation or sexual commitment however, the genetic disruption of ap2-g2 stalls normal gametocyte development beyond stage III (39,59). In pre-stage II gametocytes, 3% of the upstream AP2-G2 binding sites were enriched with H3K36me2/3.…”

ThePlasmodiumNOT1-G Paralogue Acts as an Essential Nexus for Sexual Stage Maturation and Parasite Transmission

“…However, these asexual blood stage parasites cannot be productively transmitted back to the mosquito. For this, a fraction of blood stage parasites will commit to a sexual developmental program to produce male and female gametocytes, which is dependent upon the ApiAP2-G specific transcription factor [4][5][6] and is also affected by ApiAP2-G2, which is thought to act as a transcriptional repressor of off-stage transcription [7][8][9]. In addition, several other protein-and epigenetic-based regulators are central to the commitment to sexual stage development (reviewed in [10,11]).…”