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

Gilda Padalino Orcid Logo, Cassandra A. Celatka, Hugh Y. Rienhoff Jr., Jay H. Kalin, Philip A. Cole, Damien Lassalle, Josephine Forde-Thomas, Iain W. Chalmers Orcid Logo, Andrea Brancale Orcid Logo, Christoph Grunau Orcid Logo, Karl F. Hoffmann Orcid Logo

Wellcome Open Research, Volume: 8, Start page: 146

Swansea University Author: Gilda Padalino Orcid Logo

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Abstract

Background: Schistosoma mansoni, 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 S. mansoni epigenetic machine...

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Published in: Wellcome Open Research
ISSN: 2398-502X
Published: F1000 Research Ltd 2023
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa64428
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Abstract: Background: Schistosoma mansoni, 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 S. mansoni 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. Methods: In vitro whole organism assays were used to assess the anti-schistosomal activity of 39 Homo sapiens 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. Results: Amongst this collection of small molecules, compound 33 was the most potent in reducing ex vivo viabilities of schistosomula, juveniles, miracidia and adults. At its sub-lethal concentration to adults (3.13 µM), compound 33 also significantly impacted oviposition, ovarian as well as vitellarian architecture and gonadal/neoblast stem cell proliferation. ATAC-seq analysis of adults demonstrated that compound 33 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 ex vivo 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 33 treatment. Conclusions: This work confirms the importance of histone methylation in S. mansoni lifecycle transitions, suggesting that evaluation of LSD1 - targeting epi-drugs may facilitate the search for next-generation anti-schistosomal drugs. The ability of compound 33 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.
Keywords: Lysine Specific Demethylase 1, epigenetics, ATAC-seq, anthelmintics
College: Faculty of Medicine, Health and Life Sciences
Funders: KFH, GP and AB thank the Welsh Government, Life Sciences Research Network Wales scheme and the Wellcome Trust (107475/Z/15/Z) for financially supporting this project. JHK and PAC thank the NIH (GM62437). DL and CG acknowledge the support provided by the framework of the "Laboratoires d'Excellences (LABEX)" TULIP (ANR‐10‐LABX‐41). With the support of LabEx CeMEB, an ANR « Investissements d’avenir » program (ANR-10-LABX-04-01) and its Plateforme Epigénomique Environnementale. Eve Toulza and the Bio-Environment platform team performed the Illumina sequencing whose cost was covered by the Joy Welch Research Fund: Post-doctoral Grants 2021/22- Funding Call.
Start Page: 146