Abstract
BackgroundThe Plasmodium sexual gametocyte stages are the only transmissible form of the malaria parasite and are thus responsible for the continued transmission of the disease. Gametocytes undergo extensive functional and morphological changes from commitment to maturity, directed by an equally extensive control program. However, the processes that drive the differentiation and development of the gametocyte post-commitment, remain largely unexplored. A previous study reported enrichment of H3K36 di- and tri-methylated (H3K36me2&3) histones in early-stage gametocytes. Using chromatin immunoprecipitation followed by high-throughput sequencing, we identify a stage-specific association between these repressive histone modifications and transcriptional reprogramming that define a stage II gametocyte transition point.ResultsHere, we show that H3K36me2 and H3K36me3 from stage II gametocytes are associated with repression of genes involved in asexual proliferation and sexual commitment, indicating that H3K36me2&3-mediated repression of such genes is essential to the transition from early gametocyte differentiation to intermediate development. Importantly, we show that the gene encoding the transcription factor AP2-G as commitment master regulator is enriched with H3K36me2&3 and actively repressed in stage II gametocytes, providing the first evidence of ap2-g gene repression in post-commitment gametocytes. Lastly, we associate the enhanced potency of the pan-selective Jumonji inhibitor JIB-04 in gametocytes with the inhibition of histone demethylation including H3K36me2&3 and a disruption of normal transcriptional programs.ConclusionsTaken together, our results provide the first description of an association between global gene expression reprogramming and histone post-translational modifications during P. falciparum early sexual development. The stage II gametocyte-specific abundance of H3K36me2&3 manifests predominantly as an independent regulatory mechanism targeted towards genes that are repressed post-commitment. H3K36me2&3-associated repression of genes is therefore involved in key transcriptional shifts that accompany the transition from early gametocyte differentiation to intermediate development.
Highlights
The Plasmodium sexual gametocyte stages are the only transmissible form of the malaria parasite and are responsible for the continued transmission of the disease
We find that only 18% of the H3K36me2&3-enriched genes are activated by AP2-G or heterochromatin protein 1 (HP1) depletion during commitment, implying the H3K36me2&3-associated transcriptional repression of commitment-related genes in stage II gametocytes are irrespective of mechanisms by which they were activated in the preceding commitment steps
While we find that H3K36me2&3 function largely independently of other regulatory mechanisms, we do find an association between these histone post-translational modification (hPTM) and AP2-G2 regulation in gametocytes as reported previously for asexual parasites [58] as well as a link between H3K36me2&3 and the formation of heterochromatin in early gametocytes in accordance with similar observations in other organisms [75, 88, 89]
Summary
The Plasmodium sexual gametocyte stages are the only transmissible form of the malaria parasite and are responsible for the continued transmission of the disease. Malaria eradication relies on preventing the transmission of Plasmodium parasites between human hosts, facilitated by the mosquito vector. Malaria parasites exist either as the asexual proliferative stages, responsible for the symptoms of malaria, or as sexually differentiated, transmissible gametocytes [2, 3]. The extended 10- to 12-day process of gametocyte development is characterised by morphologically distinct stages (I–V) and is unique to the human malaria parasite, Plasmodium falciparum. Mature gametocytes are the only stage that can be transmitted by the mosquito vector and as such, the process of gametocytogenesis is an attractive target for the development of transmission-blocking strategies [4,5,6]
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