The 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. Here, 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. Taken 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.

中文翻译：

---

H3K36甲基化重编程基因表达以驱动恶性疟原虫的早期配子体发育

疟原虫性配子体阶段是疟疾寄生虫的唯一可传播形式，因此是该疾病持续传播的原因。在同样广泛的控制程序的指导下，配子体从承诺到成熟经历了广泛的功能和形态变化。然而，驱动配子体的分化和发育的过程在很大程度上仍未被探索。先前的一项研究报道了早期配子体中 H3K36 二甲基化和三甲基化 (H3K36me2&3) 组蛋白的富集。使用染色质免疫沉淀和高通量测序，我们确定了这些抑制性组蛋白修饰与定义 II 期配子体转变点的转录重编程之间的阶段特异性关联。这里，我们表明，来自 II 期配子体的 H3K36me2 和 H3K36me3 与参与无性增殖和性承诺的基因的抑制有关，表明 H3K36me2&3 介导的这些基因的抑制对于从早期配子体分化到中期发育的转变至关重要。重要的是，我们表明编码转录因子 AP2-G 作为承诺主调节因子的基因富含 H3K36me2&3，并在 II 期配子体中被积极抑制，提供了承诺后配子体中 ap2-g 基因抑制的第一个证据。最后，我们将泛选择性 Jumonji 抑制剂 JIB-04 在配子体中的增强效力与组蛋白去甲基化（包括 H3K36me2&3）的抑制和正常转录程序的破坏联系起来。综合起来，我们的研究结果首次描述了恶性疟原虫早期性发育过程中全局基因表达重编程与组蛋白翻译后修饰之间的关联。H3K36me2&3 的 II 期配子体特异性丰度主要表现为一种独立的调节机制，针对在承诺后被抑制的基因。因此，H3K36me2&3 相关的基因抑制参与了伴随从早期配子体分化到中间发育的转变的关键转录转变。3主要表现为一种独立的调节机制，针对在承诺后被抑制的基因。因此，H3K36me2&3 相关的基因抑制参与了伴随从早期配子体分化到中间发育的转变的关键转录转变。3主要表现为一种独立的调节机制，针对在承诺后被抑制的基因。因此，H3K36me2&3 相关的基因抑制参与了伴随从早期配子体分化到中间发育的转变的关键转录转变。