Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2020 |
| Outros Autores: | , , , , , , , , , , , , , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Institucional da FIOCRUZ (ARCA) |
| Texto Completo: | https://www.arca.fiocruz.br/handle/icict/42596 |
Resumo: | Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Bioquímica Médica Leopoldo de Meis. Programa de Biologia Molecular e Biotecnologia. Rio de Janeiro, RJ, Brasil / German Cancer Research Center. Division of Epigenetics. Heidelberg, Germany. |
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Coutinho Carneiro, VitorSilva, Isabel Caetano de Abreu daAmaral, Murilo SenaPereira, Adriana S. A.Silveira, Gilbert OliveiraPires, David da SilvaAlmeida, Sergio VerjovskiDekker, Frank J.Rotili, DanteMai, AntonelloTorres, Eduardo José LopesRobaa, DinaSippl, WolfgangPierce, Raymond J.Borrello, M. TeresaGanesan, A.Lancelot, JulienThiengo, SilvanaFernandez, Monica AmmonVicentino, Amanda Roberta RevoredoMourão, Marina MoraesCoelho, Fernanda SalesFantappié, Marcelo Rosado2020-08-07T18:18:09Z2020-08-07T18:18:09Z2020CARNEIRO, Vitor Coutinho et al. Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni. PLoS Neglected Tropical Diseases, v. 14, n. 7, p. 1-29, 2020.1935-2727https://www.arca.fiocruz.br/handle/icict/4259610.1371/journal.pntd.00083321935-2735engPublic Library of ScienceInibição farmacológicaLisina a desmetilase 1 (LSD1)Desregulamentação transcricionaAlterações ultraestruturaisSchistosoma mansoniPharmacological inhibitionSchistosoma mansoniLysine-specific demethylase 1Transcriptional deregulationUltrastructural alterationsPharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoniinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleUniversidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Bioquímica Médica Leopoldo de Meis. Programa de Biologia Molecular e Biotecnologia. Rio de Janeiro, RJ, Brasil / German Cancer Research Center. Division of Epigenetics. Heidelberg, Germany.Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Bioquímica Médica Leopoldo de Meis. Programa de Biologia Molecular e Biotecnologia. Rio de Janeiro, RJ, Brasil.Instituto Butantan. Laboratório de Parasitologia. São Paulo, SP, Brasil.Instituto Butantan. Laboratório de Parasitologia. São Paulo, SP, Brasil / Universidade de São Paulo. Instituto de Química. Departamento de Bioquímica. São Paulo, SP, Brasil.Instituto Butantan. Laboratório de Parasitologia. São Paulo, SP, Brasil / Universidade de São Paulo. Instituto de Química. Departamento de Bioquímica. São Paulo, SP, Brasil.Instituto Butantan. Laboratório de Parasitologia. São Paulo, SP, Brasil.Instituto Butantan. Laboratório de Parasitologia. São Paulo, SP, Brasil / Universidade de São Paulo. Instituto de Química. Departamento de Bioquímica. São Paulo, SP, Brasil.University of Groningen. Department of Chemical and Pharmaceutical Biology. Antonius Deusinglaan, AV Groningen, Netherlands.Sapienza University of Rome. Department of Drug Chemistry and Technologies. Rome, Italy.Sapienza University of Rome. Department of Drug Chemistry and Technologies. Rome, Italy.Universidade do Estado do Rio de Janeiro. Faculdade de Ciências Médicas. Laboratório de Helmintologia Romero Lascasas Porto. Rio de Janeiro, RJ, Brasil.Martin Luther University of Halle-Wittenberg. Institute of Pharmacy. Germany.Martin Luther University of Halle-Wittenberg. Institute of Pharmacy. Germany.Université de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019—UMR 9017—CIIL—Centre d’Infection et d’Immunitè de Lille. Lille, France.Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Universite´ and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France.University of East Anglia. School of Pharmacy. Norwich NR4 7TJ, United Kingdom.Université de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019—UMR 9017—CIIL—Centre d’Infection et d’Immunitè de Lille. Lille, France.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Malacologia. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Malacologia. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Bioquímica Médica Leopoldo de Meis. Programa de Biologia Molecular e Biotecnologia. Rio de Janeiro, RJ, Brasil.Fundacão Oswaldo Cruz. Instituto Rene Rachou. Grupo de Helmintologia e Malacologia Médica. Belo Horizonte, MG, Brasil.Fundacão Oswaldo Cruz. Instituto Rene Rachou. Grupo de Helmintologia e Malacologia Médica. Belo Horizonte, MG, Brasil.Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Bioquímica Médica Leopoldo de Meis. Programa de Biologia Molecular e Biotecnologia. Rio de Janeiro, RJ, Brasil.Treatment and control of schistosomiasis still rely on only one effective drug, praziquantel (PZQ) and, due to mass treatment, the increasing risk of selecting for schistosome strains that are resistant to PZQ has alerted investigators to the urgent need to develop novel therapeutic strategies. The histone-modifying enzymes (HMEs) represent promising targets for the development of epigenetic drugs against Schistosoma mansoni. In the present study, we targeted the S. mansoni lysine-specific demethylase 1 (SmLSD1), a transcriptional corepressor, using a novel and selective synthetic inhibitor, MC3935, which was used to treat schistosomula and adult worms in vitro. By using cell viability assays and optical and electron microscopy, we showed that treatment with MC3935 affected parasite motility, egg-laying, tegument, and cellular organelle structures, culminating in the death of schistosomula and adult worms. In silico molecular modeling and docking analysis suggested that MC3935 binds to the catalytic pocket of SmLSD1. Western blot analysis revealed that MC3935 inhibited SmLSD1 demethylation activity of H3K4me1/2. Knockdown of SmLSD1 by RNAi recapitulated MC3935 phenotypes in adult worms. RNA-Seq analysis of MC3935-treated parasites revealed significant differences in gene expression related to critical biological processes. Collectively, our findings show that SmLSD1 is a promising drug target for the treatment of schistosomiasis and strongly support the further development and in vivo testing of selective schistosome LSD1 inhibitors.info:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-82991https://www.arca.fiocruz.br/bitstream/icict/42596/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALMuriloSAmaral_AdrianaAPereira_etal_IOC_2020.pdfMuriloSAmaral_AdrianaAPereira_etal_IOC_2020.pdfapplication/pdf4101847https://www.arca.fiocruz.br/bitstream/icict/42596/2/MuriloSAmaral_AdrianaAPereira_etal_IOC_2020.pdf30bc408af9a291afee87586356ae106bMD52TEXTMuriloSAmaral_AdrianaAPereira_etal_IOC_2020.pdf.txtMuriloSAmaral_AdrianaAPereira_etal_IOC_2020.pdf.txtExtracted 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| dc.title.pt_BR.fl_str_mv |
Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni |
| title |
Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni |
| spellingShingle |
Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni Coutinho Carneiro, Vitor Inibição farmacológica Lisina a desmetilase 1 (LSD1) Desregulamentação transcriciona Alterações ultraestruturais Schistosoma mansoni Pharmacological inhibition Schistosoma mansoni Lysine-specific demethylase 1 Transcriptional deregulation Ultrastructural alterations |
| title_short |
Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni |
| title_full |
Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni |
| title_fullStr |
Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni |
| title_full_unstemmed |
Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni |
| title_sort |
Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni |
| author |
Coutinho Carneiro, Vitor |
| author_facet |
Coutinho Carneiro, Vitor Silva, Isabel Caetano de Abreu da Amaral, Murilo Sena Pereira, Adriana S. A. Silveira, Gilbert Oliveira Pires, David da Silva Almeida, Sergio Verjovski Dekker, Frank J. Rotili, Dante Mai, Antonello Torres, Eduardo José Lopes Robaa, Dina Sippl, Wolfgang Pierce, Raymond J. Borrello, M. Teresa Ganesan, A. Lancelot, Julien Thiengo, Silvana Fernandez, Monica Ammon Vicentino, Amanda Roberta Revoredo Mourão, Marina Moraes Coelho, Fernanda Sales Fantappié, Marcelo Rosado |
| author_role |
author |
| author2 |
Silva, Isabel Caetano de Abreu da Amaral, Murilo Sena Pereira, Adriana S. A. Silveira, Gilbert Oliveira Pires, David da Silva Almeida, Sergio Verjovski Dekker, Frank J. Rotili, Dante Mai, Antonello Torres, Eduardo José Lopes Robaa, Dina Sippl, Wolfgang Pierce, Raymond J. Borrello, M. Teresa Ganesan, A. Lancelot, Julien Thiengo, Silvana Fernandez, Monica Ammon Vicentino, Amanda Roberta Revoredo Mourão, Marina Moraes Coelho, Fernanda Sales Fantappié, Marcelo Rosado |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author |
| dc.contributor.author.fl_str_mv |
Coutinho Carneiro, Vitor Silva, Isabel Caetano de Abreu da Amaral, Murilo Sena Pereira, Adriana S. A. Silveira, Gilbert Oliveira Pires, David da Silva Almeida, Sergio Verjovski Dekker, Frank J. Rotili, Dante Mai, Antonello Torres, Eduardo José Lopes Robaa, Dina Sippl, Wolfgang Pierce, Raymond J. Borrello, M. Teresa Ganesan, A. Lancelot, Julien Thiengo, Silvana Fernandez, Monica Ammon Vicentino, Amanda Roberta Revoredo Mourão, Marina Moraes Coelho, Fernanda Sales Fantappié, Marcelo Rosado |
| dc.subject.other.pt_BR.fl_str_mv |
Inibição farmacológica Lisina a desmetilase 1 (LSD1) Desregulamentação transcriciona Alterações ultraestruturais Schistosoma mansoni |
| topic |
Inibição farmacológica Lisina a desmetilase 1 (LSD1) Desregulamentação transcriciona Alterações ultraestruturais Schistosoma mansoni Pharmacological inhibition Schistosoma mansoni Lysine-specific demethylase 1 Transcriptional deregulation Ultrastructural alterations |
| dc.subject.en.pt_BR.fl_str_mv |
Pharmacological inhibition Schistosoma mansoni Lysine-specific demethylase 1 Transcriptional deregulation Ultrastructural alterations |
| description |
Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Bioquímica Médica Leopoldo de Meis. Programa de Biologia Molecular e Biotecnologia. Rio de Janeiro, RJ, Brasil / German Cancer Research Center. Division of Epigenetics. Heidelberg, Germany. |
| publishDate |
2020 |
| dc.date.accessioned.fl_str_mv |
2020-08-07T18:18:09Z |
| dc.date.available.fl_str_mv |
2020-08-07T18:18:09Z |
| dc.date.issued.fl_str_mv |
2020 |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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publishedVersion |
| dc.identifier.citation.fl_str_mv |
CARNEIRO, Vitor Coutinho et al. Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni. PLoS Neglected Tropical Diseases, v. 14, n. 7, p. 1-29, 2020. |
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https://www.arca.fiocruz.br/handle/icict/42596 |
| dc.identifier.issn.pt_BR.fl_str_mv |
1935-2727 |
| dc.identifier.doi.none.fl_str_mv |
10.1371/journal.pntd.0008332 |
| dc.identifier.eissn.none.fl_str_mv |
1935-2735 |
| identifier_str_mv |
CARNEIRO, Vitor Coutinho et al. Pharmacological inhibition of lysine-specific demethylase 1 (LSD1) induces global transcriptional deregulation and ultrastructural alterations that impair viability in Schistosoma mansoni. PLoS Neglected Tropical Diseases, v. 14, n. 7, p. 1-29, 2020. 1935-2727 10.1371/journal.pntd.0008332 1935-2735 |
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https://www.arca.fiocruz.br/handle/icict/42596 |
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eng |
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eng |
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info:eu-repo/semantics/openAccess |
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openAccess |
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Public Library of Science |
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Public Library of Science |
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