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

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.

doi:10.12688/wellcomeopenres.18826.1

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

Gilda Padalino

, Cassandra A. Celatka, Hugh Y. Rienhoff Jr., Jay H. Kalin, Philip A. Cole, Damien Lassalle, Josephine Forde-Thomas, Iain W. Chalmers

, Andrea Brancale

, Christoph Grunau

, Karl F. Hoffmann

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

Swansea University Author: Gilda Padalino

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DOI (Published version): 10.12688/wellcomeopenres.18826.1

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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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.</abstract><type>Journal Article</type><journal>Wellcome Open Research</journal><volume>8</volume><journalNumber/><paginationStart>146</paginationStart><paginationEnd/><publisher>F1000 Research Ltd</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>2398-502X</issnElectronic><keywords>Lysine Specific Demethylase 1, epigenetics, ATAC-seq, anthelmintics</keywords><publishedDay>30</publishedDay><publishedMonth>3</publishedMonth><publishedYear>2023</publishedYear><publishedDate>2023-03-30</publishedDate><doi>10.12688/wellcomeopenres.18826.1</doi><url>http://dx.doi.org/10.12688/wellcomeopenres.18826.1</url><notes/><college>COLLEGE NANME</college><department>Pharmacy</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>PHAR</DepartmentCode><institution>Swansea University</institution><apcterm/><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. 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spelling	v2 64428 2023-09-05 Chemical modulation of Schistosoma mansoni lysine specific demethylase 1 (SmLSD1) induces wide-scale biological and epigenomic changes 7e5526209f02734f57ba19b0d17604ec 0000-0001-8580-1293 Gilda Padalino Gilda Padalino true false 2023-09-05 PHAR 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. Journal Article Wellcome Open Research 8 146 F1000 Research Ltd 2398-502X Lysine Specific Demethylase 1, epigenetics, ATAC-seq, anthelmintics 30 3 2023 2023-03-30 10.12688/wellcomeopenres.18826.1 http://dx.doi.org/10.12688/wellcomeopenres.18826.1 COLLEGE NANME Pharmacy COLLEGE CODE PHAR Swansea University 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. 2024-01-08T14:03:57.2699256 2023-09-05T16:07:00.6644426 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Pharmacy Gilda Padalino 0000-0001-8580-1293 1 Cassandra A. Celatka 2 Hugh Y. Rienhoff Jr. 3 Jay H. Kalin 4 Philip A. Cole 5 Damien Lassalle 6 Josephine Forde-Thomas 7 Iain W. Chalmers 0000-0001-8674-1181 8 Andrea Brancale 0000-0002-9728-3419 9 Christoph Grunau 0000-0003-3180-344x 10 Karl F. Hoffmann 0000-0002-3932-5502 11 64428__28754__2587cf2b7e2a477ea7610bcdad3039b0.pdf 64428.VOR.pdf 2023-10-10T11:09:24.2597120 Output 9577585 application/pdf Version of Record true © 2023 Padalino G et al. Distributed under the terms of a Creative Commons Attribution 4.0 License (CC BY 4.0). true eng https://creativecommons.org/licenses/by/4.0/
title	Chemical modulation of Schistosoma mansoni lysine specific demethylase 1 (SmLSD1) induces wide-scale biological and epigenomic changes
spellingShingle	Chemical modulation of Schistosoma mansoni lysine specific demethylase 1 (SmLSD1) induces wide-scale biological and epigenomic changes Gilda Padalino
title_short	Chemical modulation of Schistosoma mansoni lysine specific demethylase 1 (SmLSD1) induces wide-scale biological and epigenomic changes
title_full	Chemical modulation of Schistosoma mansoni lysine specific demethylase 1 (SmLSD1) induces wide-scale biological and epigenomic changes
title_fullStr	Chemical modulation of Schistosoma mansoni lysine specific demethylase 1 (SmLSD1) induces wide-scale biological and epigenomic changes
title_full_unstemmed	Chemical modulation of Schistosoma mansoni lysine specific demethylase 1 (SmLSD1) induces wide-scale biological and epigenomic changes
title_sort	Chemical modulation of Schistosoma mansoni lysine specific demethylase 1 (SmLSD1) induces wide-scale biological and epigenomic changes
author_id_str_mv	7e5526209f02734f57ba19b0d17604ec
author_id_fullname_str_mv	7e5526209f02734f57ba19b0d17604ec_***_Gilda Padalino
author	Gilda Padalino
author2	Gilda Padalino Cassandra A. Celatka Hugh Y. Rienhoff Jr. Jay H. Kalin Philip A. Cole Damien Lassalle Josephine Forde-Thomas Iain W. Chalmers Andrea Brancale Christoph Grunau Karl F. Hoffmann
format	Journal article
container_title	Wellcome Open Research
container_volume	8
container_start_page	146
publishDate	2023
institution	Swansea University
issn	2398-502X
doi_str_mv	10.12688/wellcomeopenres.18826.1
publisher	F1000 Research Ltd
college_str	Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id	facultyofmedicinehealthandlifesciences
hierarchy_top_title	Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id	facultyofmedicinehealthandlifesciences
hierarchy_parent_title	Faculty of Medicine, Health and Life Sciences
department_str	Swansea University Medical School - Pharmacy{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Pharmacy
url	http://dx.doi.org/10.12688/wellcomeopenres.18826.1
document_store_str	1
active_str	0
description	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.
published_date	2023-03-30T14:03:58Z
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Chemical modulation of Schistosoma mansoni lysine specific demethylase 1 (SmLSD1) induces wide-scale biological and epigenomic changes

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