Hierarchical transcriptional control regulates Plasmodium falciparum sexual differentiation

Abstract

BackgroundMalaria pathogenesis relies on sexual gametocyte forms of the malaria parasite to be transmitted between the infected human and the mosquito host but the molecular mechanisms controlling gametocytogenesis remains poorly understood. Here we provide a high-resolution transcriptome of Plasmodium falciparum as it commits to and develops through gametocytogenesis.ResultsThe gametocyte-associated transcriptome is significantly different from that of the asexual parasites, with dynamic gene expression shifts characterizing early, intermediate and late-stage gametocyte development and results in differential timing for sex-specific transcripts. The transcriptional dynamics suggest strict transcriptional control during gametocytogenesis in P. falciparum, which we propose is mediated by putative regulators including epigenetic mechanisms (driving active repression of proliferation-associated processes) and a cascade-like expression of ApiAP2 transcription factors.ConclusionsThe gametocyte transcriptome serves as the blueprint for sexual differentiation and will be a rich resource for future functional studies on this critical stage of Plasmodium development, as the intraerythrocytic transcriptome has been for our understanding of the asexual cycle.

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

“…Stage I/II gametocytes express exported proteins involved in sexual stage-speci c iRBC remodeling 42 . Enzymes of the oxidative tricarboxylic acid (TCA) cycle are upregulated in gametocytes 39,44,45 , consistent with their increased dependence on the TCA cycle for energy production 50 . Factors involved in protein synthesis, mitochondrial function and translational repression are upregulated in females [46][47][48][49] , in line with the increased abundance of ribosomes 12 , enlarged mitochondrion 12,51 and large number of translationally repressed transcripts in these stages 46 .…”

“…Regarding the complex process of sexual differentiation, mRNA and protein expression pro ling studies conducted mainly on late stage gametocytes [39][40][41][42][43] , but also on early stages 42,43 or across gametocyte maturation 44,45 , identi ed hundreds of genes and proteins speci cally up-or downregulated compared to asexual blood stages, or between female and male gametocytes [46][47][48][49] . Stage I/II gametocytes express exported proteins involved in sexual stage-speci c iRBC remodeling 42 .…”

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

“…Stage I/II gametocytes express exported proteins involved in sexual stage-specific iRBC remodeling 42 . Enzymes of the oxidative tricarboxylic acid (TCA) cycle are upregulated in gametocytes 39,44,45 , consistent with their increased dependence on the TCA cycle for energy production 50 . Factors involved in protein synthesis, mitochondrial function and translational repression are upregulated in females 46-49 , in line with the increased abundance of ribosomes 12 , enlarged mitochondrion 12,51 and large number of translationally repressed transcripts in these stages 46 .…”

“…Regarding the complex process of sexual differentiation, mRNA and protein expression profiling studies conducted mainly on late stage gametocytes 39-43 , but also on early stages 42,43 or across gametocyte maturation 44,45 , identified hundreds of genes and proteins specifically up- or downregulated compared to asexual blood stages, or between female and male gametocytes 46-49 . Stage I/II gametocytes express exported proteins involved in sexual stage-specific iRBC remodeling 42 .…”

“…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 .…”