Histone methylation changes are required for life cycle progression in the human parasite Schistosoma mansoni

Abstract

Epigenetic mechanisms and chromatin structure play an important role in development. Their impact is therefore expected to be strong in parasites with complex life cycles and multiple, strikingly different, developmental stages, i.e. developmental plasticity. Some studies have already described how the chromatin structure, through histone modifications, varies from a developmental stage to another in a few unicellular parasites. While H3K4me3 profiles remain relatively constant, H3K27 trimethylation and bivalent methylation show strong variation. Inhibitors (A366 and GSK343) of H3K27 histone methyltransferase activity in S. mansoni efficiently blocked miracidium to sporocyst transition indicating that H3K27 trimethylation is required for life cycle progression. As S. mansoni is a multicellular parasite that significantly affects both the health and economy of endemic areas, a better understanding of fluke developmental processes within the definitive host will likely highlight novel disease control strategies. Towards this goal, we also studied H4K20me1 in female cercariae and adults. In particular, we found that bivalent trimethylation of H3K4 and H3K27 at the transcription start site of genes is a landmark of the cercarial stage. In cercariae, H3K27me3 presence and strong enrichment in H4K20me1 over long regions (10–100 kb) is associated with development related genes. Here, we provide a broad overview of the chromatin structure of a metazoan parasite throughout its most important lifecycle stages. The five developmental stages studied here present distinct chromatin structures, indicating that histone methylation plays an important role during development. Hence, components of the histone methylation (and demethylation) machinery may provide suitable Schistosomiasis control targets.

Epigenetic and parasitological parameters are modulated in EBi3-/- mice infected with Schistosoma mansoni

“…As different intensities of interleukins are detected during schistosomiasis depending on mouse lineage, immunological profile might induce alterations in the signaling pathways of worms allowing adaptation to the host. The presence of different epigenetic marks and changes in the patterns of these marks are involved in the transition of the evolutionary stages of S. mansoni and host-parasite interaction; H3K4me3 and H3K27me3 show greater variation and influence in the transformation of the parasite among phases [14,15]. Epigenator molecules native to intracellular parasites such as protozoa trigger into host new metabolic pathways or interfere inducing initiator host proteins to modify metabolism and promote an environment suitable for parasite reproduction [16].…”

Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni

“…Patterns of specific lysine methyl 106 modifications are achieved by a precise lysine methylation system, consisting of proteins that 107 add, remove and recognize the specific lysine methyl marks. Importantly, histone lysine 108 methylation [14][15][16] and demethylation [17] have been recently demonstrated to be potential 109 drug targets against S. mansoni. 110…”

Schistosoma mansonilysine specific demethylase 1 (SmLSD1) is a druggable target involved in parasite survival, oviposition and stem cell proliferation

“…Studies of the S. mansoni lifecycle have shown that transitions between, and development within, both intermediate and definitive hosts are processes carefully regulated by epigenetic factors [17,18,23,[72][73][74]. While a critical role for histone methylation and demethylation in these processes has been demonstrated [19][20][21]23], the specific contributions of enzymes catalysing these reversible post-translational modifications have not been thoroughly characterised. Following on from our previous investigations demonstrating that anti-neoplastic anthracyclines could bind to the target pocket of SmLSD1 and kill multiple schistosome lifecycle stages [19], we pursued the evaluation of 39 HsLSD1 inhibitors as potentially more potent anti-schistosomals.…”