Inhibition of histone methyltransferase EZH2 in Schistosoma mansoni in vitro by GSK343 reduces egg laying and decreases the expression of genes implicated in DNA replication and noncoding RNA metabolism

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dc.contributorLab. Parasitologiapt_BR
dc.contributor.authorPereira, Adriana da Silva Andradept_BR
dc.contributor.authorAmaral, Murilo Senapt_BR
dc.contributor.authorVasconcelos, Elton José Rosas dept_BR
dc.contributor.authorPires, David da Silvapt_BR
dc.contributor.authorAsif, Humapt_BR
dc.contributor.authorSilva, Lucas Ferreira dapt_BR
dc.contributor.authorVicente, David Abraham Moralespt_BR
dc.contributor.authorCarneiro, Vitor Coutinhopt_BR
dc.contributor.authorAngeli, Cláudia Blanespt_BR
dc.contributor.authorPalmisano, Giuseppept_BR
dc.contributor.authorFantappíé, Marcelo Rosadopt_BR
dc.contributor.authorPierce, Raymond Johnpt_BR
dc.contributor.authorSetubal, João Carlospt_BR
dc.contributor.authorVerjovski-Almeida, Sergiopt_BR
dc.date.accessioned2020-07-09T21:21:54Z-
dc.date.available2020-07-09T21:21:54Z-
dc.date.issued2018pt_BR
dc.identifier.citationPereira ASA, Amaral MS, Vasconcelos EJR, Pires DS, Asif H, Silva LF, et al. Inhibition of histone methyltransferase EZH2 in Schistosoma mansoni in vitro by GSK343 reduces egg laying and decreases the expression of genes implicated in DNA replication and noncoding RNA metabolism. Plos Neglect. Trop. Dis.. 2018;12(10):e0006873. doi:10.1371/journal.pntd.0006873.pt_BR
dc.identifier.urihttps://repositorio.butantan.gov.br/handle/butantan/2603-
dc.description.abstractBackground The possibility of emergence of praziquantel-resistant Schistosoma parasites and the lack of other effective drugs demand the discovery of new schistosomicidal agents. In this context the study of compounds that target histone-modifying enzymes is extremely promising. Our aim was to investigate the effect of inhibition of EZH2, a histone methyltransferase that is involved in chromatin remodeling processes and gene expression control; we tested different developmental forms of Schistosoma mansoni using GKS343, a selective inhibitor of EZH2 in human cells. Methodology/Principal findings Adult male and female worms and schistosomula were treated with different concentrations of GSK343 for up to two days in vitro. Western blotting showed a decrease in the H3K27me3 histone mark in all three developmental forms. Motility, mortality, pairing and egg laying were employed as schistosomicidal parameters for adult worms. Schistosomula viability was evaluated with propidium iodide staining and ATP quantification. Adult worms showed decreased motility when exposed to GSK343. Also, an approximate 40% reduction of egg laying by GSK343-treated females was observed when compared with controls (0.1% DMSO). Scanning electron microscopy showed the formation of bulges and bubbles throughout the dorsal region of GSK343-treated adult worms. In schistosomula the body was extremely contracted with the presence of numerous folds, and growth was markedly slowed. RNA-seq was applied to identify the metabolic pathways affected by GSK343 sublethal doses. GSK343-treated adult worms showed significantly altered expression of genes related to transmembrane transport, cellular homeostasis and egg development. In females, genes related to DNA replication and noncoding RNA metabolism processes were downregulated. Schistosomula showed altered expression of genes related to cell adhesion and membrane synthesis pathways. Conclusions/Significance The results indicated that GSK343 presents in vitro activities against S. mansoni, and the characterization of EZH2 as a new potential molecular target establishes EZH2 inhibitors as part of a promising new group of compounds that could be used for the development of schistosomicidal agents. Author summarypt_BR
dc.description.sponsorship(FP7) Seventh Framework Programme of the European Commissionpt_BR
dc.description.sponsorship(CAPES) Coordenação de Aperfeiçoamento de Pessoal de Nível Superiorpt_BR
dc.description.sponsorship(FAPESP) Fundação de Amparo à Pesquisa do Estado de São Paulopt_BR
dc.description.sponsorship(CNPq) Conselho Nacional de Desenvolvimento Científico e Tecnológicopt_BR
dc.format.extente0006873pt_BR
dc.language.isoEnglishpt_BR
dc.relation.ispartofPlos Neglected Tropical Diseasespt_BR
dc.rightsOpen accesspt_BR
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/pt_BR
dc.titleInhibition of histone methyltransferase EZH2 in Schistosoma mansoni in vitro by GSK343 reduces egg laying and decreases the expression of genes implicated in DNA replication and noncoding RNA metabolismpt_BR
dc.typeArticlept_BR
dc.rights.licenseCC BYpt_BR
dc.identifier.doi10.1371/journal.pntd.0006873pt_BR
dc.identifier.urlhttps://doi.org/10.1371/journal.pntd.0006873pt_BR
dc.contributor.external(USP) Universidade de São Paulopt_BR
dc.contributor.external(UFRJ) Universidade Federal do Rio de Janeiropt_BR
dc.contributor.externalInstitut Pasteur de Lillept_BR
dc.identifier.citationvolume12pt_BR
dc.identifier.citationissue10pt_BR
dc.relation.ispartofabbreviatedPlos Neglect Trop Dispt_BR
dc.identifier.citationabntv. 12, n. 10, e0006873, 2018pt_BR
dc.identifier.citationvancouver2018;12(10):e0006873pt_BR
dc.contributor.butantanAmaral, Murilo Sena|:Técnico|:Lab. Parasitologia|:pt_BR
dc.contributor.butantanVasconcelos, Elton José Rosas de|:Aluno|:Lab. Parasitologia|:pt_BR
dc.contributor.butantanPires, David da Silva|:Técnico|:Lab. Parasitologia|:pt_BR
dc.contributor.butantanAsif, Huma|:Aluno|:Lab. Parasitologia|:pt_BR
dc.contributor.butantanSilva, Lucas Ferreira da|:Aluno|:Lab. Parasitologia|:pt_BR
dc.contributor.butantanVicente, David Abraham Morales|:Aluno|:Lab. Parasitologia|:pt_BR
dc.contributor.butantanVerjovski-Almeida, Sergio|:Pesquisador|:Lab. Parasitologia|:Autor de correspondênciapt_BR
dc.contributor.butantanPereira, Adriana da Silva Andrade|:Aluno|:Lab. Parasitologia|:PrimeiroAutorpt_BR
dc.sponsorship.butantan(CNPq) Conselho Nacional de Desenvolvimento Científico e Tecnológico¦¦pt_BR
dc.sponsorship.butantan(CAPES) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior¦¦001pt_BR
dc.sponsorship.butantanEuropean Union’s Seventh Framework Programme¦¦602080pt_BR
dc.sponsorship.butantan(FAPESP) Fundação de Amparo à Pesquisa do Estado de São Paulo¦¦2014/24560-8pt_BR
dc.sponsorship.butantan(FAPESP) Fundação de Amparo à Pesquisa do Estado de São Paulo¦¦2016/10046-6pt_BR
dc.sponsorship.butantan(FAPESP) Fundação de Amparo à Pesquisa do Estado de São Paulo¦¦2014/06863-3pt_BR
dc.identifier.bvsccBR78.1pt_BR
dc.identifier.bvsdbIBProdpt_BR
dc.description.dbindexedYespt_BR
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