Chemical modulation of Schistosoma mansoni lysine specific demethylase 1 (SmLSD1) induces wide-scale biological and epigenomic changes

• Published in: Wellcome open research Vol. 8; p. 146
• Main Authors: Padalino, Gilda, Celatka, Cassandra A, Rienhoff, Jr, Hugh Y, Kalin, Jay H, Cole, Philip A, Lassalle, Damien, Forde-Thomas, Josephine, Chalmers, Iain W, Brancale, Andrea, Grunau, Christoph, Hoffmann, Karl F
• Format: Journal Article
• Language: English
• Published: England F1000 Research Limited 2023; Wellcome
• Subjects: anthelmintics; ATAC-seq; eng; epigenetics; Lysine Specific Demethylase 1; Lysine Specific Demethylase 1; ATAC-seq; epigenetics; anthelmintics
• ISSN: 2398-502X; 2398-502X
• DOI: 10.12688/wellcomeopenres.18826.1

: , 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.