Padalino Gilda, Celatka Cassandra A, Rienhoff Hugh Y, Kalin Jay H, Cole Philip A, Lassalle Damien, Forde-Thomas Josephine, Chalmers Iain W, Brancale Andrea, Grunau Christoph, Hoffmann Karl F
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, Wales, CF10 3NB, UK.
Imago BioSciences, San Carlos, CA 94070, USA.
Wellcome Open Res. 2023 Mar 30;8:146. doi: 10.12688/wellcomeopenres.18826.1. eCollection 2023.
: , a parasitic worm species responsible for the neglected tropical disease schistosomiasis, undergoes strict developmental regulation of gene expression that is carefully controlled by both genetic and epigenetic processes. As inhibition of epigenetic machinery components impairs key transitions throughout the parasite's digenetic lifecycle, a greater understanding of how epi-drugs affect molecular processes in schistosomes could lead to the development of new anthelmintics. whole organism assays were used to assess the anti-schistosomal activity of 39 Lysine Specific Demethylase 1 (HsLSD1) inhibitors on different parasite life cycle stages. Moreover, tissue-specific stains and genomic analysis shed light on the effect of these small molecules on the parasite biology. Amongst this collection of small molecules, compound was the most potent in reducing viabilities of schistosomula, juveniles, miracidia and adults. At its sub-lethal concentration to adults (3.13 µM), compound also significantly impacted oviposition, ovarian as well as vitellarian architecture and gonadal/neoblast stem cell proliferation. ATAC-seq analysis of adults demonstrated that compound significantly affected chromatin structure (intragenic regions > intergenic regions), especially in genes differentially expressed in cell populations (e.g., germinal stem cells, hes2 stem cell progeny, S1 cells and late female germinal cells) associated with these phenotypes. KEGG analyses further highlighted that chromatin structure of genes associated with sugar metabolism as well as TGF-beta and Wnt signalling were also significantly perturbed by compound treatment. This work confirms the importance of histone methylation in lifecycle transitions, suggesting that evaluation of LSD1 - targeting epi-drugs may facilitate the search for next-generation anti-schistosomal drugs. The ability of compound to modulate chromatin structure as well as inhibit parasite survival, oviposition and stem cell proliferation warrants further investigations of this compound and its epigenetic target SmLSD1.
血吸虫，一种导致被忽视的热带病血吸虫病的寄生蠕虫物种，经历严格的基因表达发育调控，这种调控由遗传和表观遗传过程精心控制。由于抑制表观遗传机制成分会损害寄生虫双宿主生命周期中的关键转变，更深入了解表观遗传药物如何影响血吸虫的分子过程可能会导致开发新的驱虫药。使用全生物体试验评估39种赖氨酸特异性去甲基化酶1（HsLSD1）抑制剂对不同寄生虫生命周期阶段的抗血吸虫活性。此外，组织特异性染色和基因组分析揭示了这些小分子对寄生虫生物学的影响。在这组小分子中，化合物在降低血吸虫幼虫、成虫、毛蚴和成虫的活力方面最为有效。在其对成虫的亚致死浓度（3.13μM）下，化合物还显著影响产卵、卵巢以及卵黄腺结构和性腺/成体干细胞增殖。对成虫的ATAC-seq分析表明，化合物显著影响染色质结构（基因内区域>基因间区域），特别是在与这些表型相关的细胞群体（如生殖干细胞、hes2干细胞后代、S1细胞和晚期雌性生殖细胞）中差异表达的基因中。KEGG分析进一步强调，与糖代谢以及TGF-β和Wnt信号相关的基因的染色质结构也受到化合物处理的显著干扰。这项工作证实了组蛋白甲基化在生命周期转变中的重要性，表明评估靶向LSD1的表观遗传药物可能有助于寻找下一代抗血吸虫药物。化合物调节染色质结构以及抑制寄生虫存活、产卵和干细胞增殖的能力值得对该化合物及其表观遗传靶点SmLSD1进行进一步研究。
