Epigenetic changes modulate schistosome egg formation and are a novel target for reducing transmission of schistosomiasis.

Treatment and control of schistosomiasis relies on the only available drug, praziquantel, and the search for alternative chemotherapeutic agents is therefore urgent. Egg production is required for the transmission and immunopathology of schistosomiasis and females of S. mansoni lay 300 eggs daily. A...

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Autores principales:	Vitor Coutinho Carneiro, Isabel Caetano de Abreu da Silva, Eduardo José Lopes Torres, Stephany Caby, Julien Lancelot, Mathieu Vanderstraete, Silviya D Furdas, Manfred Jung, Raymond J Pierce, Marcelo Rosado Fantappié
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/510576f87bbf475a8b1ca3e4cd56c6a8
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spelling	oai:doaj.org-article:510576f87bbf475a8b1ca3e4cd56c6a82021-11-18T06:06:36ZEpigenetic changes modulate schistosome egg formation and are a novel target for reducing transmission of schistosomiasis.1553-73661553-737410.1371/journal.ppat.1004116https://doaj.org/article/510576f87bbf475a8b1ca3e4cd56c6a82014-05-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24809504/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Treatment and control of schistosomiasis relies on the only available drug, praziquantel, and the search for alternative chemotherapeutic agents is therefore urgent. Egg production is required for the transmission and immunopathology of schistosomiasis and females of S. mansoni lay 300 eggs daily. A large fraction of the total mRNA in the mature female worm encodes one eggshell protein, Smp14. We report that the nuclear receptors SmRXR1 and SmNR1 regulate Smp14 transcription through the recruitment of two histone acetyltransferases (HATs), SmGCN5 and SmCBP1. The treatment of HEK293 cells with histone deacetylase (HDAC) inhibitors (NaB or TSA) produced an 8-fold activation of the SmRXR1/SmNR1-mediated Smp14 promoter activity. Incubation with synthetic HAT inhibitors, including PU139, significantly impaired the Smp14 promoter activity in these cells. Worm pairs cultivated in the presence of PU139 exhibited limited expression of Smp14 mRNA and protein. ChIP analysis demonstrated chromatin condensation at the Smp14 promoter site in worms treated with PU139. ChIP also revealed the presence of H3K27me3 and the absence of RNA Pol II at the Smp14 promoter region in the PU139-treated worms. Most significantly, the PU139-mediated inhibition of Smp14 expression resulted in a significant number of abnormal eggs as well as defective eggs within the ootype. In addition, scanning electron microscopy revealed structural defects and unformed eggshells, and vitelline cell leakage was apparent. The dsRNAi-targeting of SmGCN5 or SmCBP1 significantly decreased Smp14 transcription and protein synthesis, which compromised the reproductive system of mature female worms, egg-laying and egg morphology. Our data strongly suggest that the inhibition of Smp14 expression targeting SmGCN5 and/or SmCBP1 represents a novel and effective strategy to control S. mansoni egg development.Vitor Coutinho CarneiroIsabel Caetano de Abreu da SilvaEduardo José Lopes TorresStephany CabyJulien LancelotMathieu VanderstraeteSilviya D FurdasManfred JungRaymond J PierceMarcelo Rosado FantappiéPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 10, Iss 5, p e1004116 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Vitor Coutinho Carneiro Isabel Caetano de Abreu da Silva Eduardo José Lopes Torres Stephany Caby Julien Lancelot Mathieu Vanderstraete Silviya D Furdas Manfred Jung Raymond J Pierce Marcelo Rosado Fantappié Epigenetic changes modulate schistosome egg formation and are a novel target for reducing transmission of schistosomiasis.
description	Treatment and control of schistosomiasis relies on the only available drug, praziquantel, and the search for alternative chemotherapeutic agents is therefore urgent. Egg production is required for the transmission and immunopathology of schistosomiasis and females of S. mansoni lay 300 eggs daily. A large fraction of the total mRNA in the mature female worm encodes one eggshell protein, Smp14. We report that the nuclear receptors SmRXR1 and SmNR1 regulate Smp14 transcription through the recruitment of two histone acetyltransferases (HATs), SmGCN5 and SmCBP1. The treatment of HEK293 cells with histone deacetylase (HDAC) inhibitors (NaB or TSA) produced an 8-fold activation of the SmRXR1/SmNR1-mediated Smp14 promoter activity. Incubation with synthetic HAT inhibitors, including PU139, significantly impaired the Smp14 promoter activity in these cells. Worm pairs cultivated in the presence of PU139 exhibited limited expression of Smp14 mRNA and protein. ChIP analysis demonstrated chromatin condensation at the Smp14 promoter site in worms treated with PU139. ChIP also revealed the presence of H3K27me3 and the absence of RNA Pol II at the Smp14 promoter region in the PU139-treated worms. Most significantly, the PU139-mediated inhibition of Smp14 expression resulted in a significant number of abnormal eggs as well as defective eggs within the ootype. In addition, scanning electron microscopy revealed structural defects and unformed eggshells, and vitelline cell leakage was apparent. The dsRNAi-targeting of SmGCN5 or SmCBP1 significantly decreased Smp14 transcription and protein synthesis, which compromised the reproductive system of mature female worms, egg-laying and egg morphology. Our data strongly suggest that the inhibition of Smp14 expression targeting SmGCN5 and/or SmCBP1 represents a novel and effective strategy to control S. mansoni egg development.
format	article
author	Vitor Coutinho Carneiro Isabel Caetano de Abreu da Silva Eduardo José Lopes Torres Stephany Caby Julien Lancelot Mathieu Vanderstraete Silviya D Furdas Manfred Jung Raymond J Pierce Marcelo Rosado Fantappié
author_facet	Vitor Coutinho Carneiro Isabel Caetano de Abreu da Silva Eduardo José Lopes Torres Stephany Caby Julien Lancelot Mathieu Vanderstraete Silviya D Furdas Manfred Jung Raymond J Pierce Marcelo Rosado Fantappié
author_sort	Vitor Coutinho Carneiro
title	Epigenetic changes modulate schistosome egg formation and are a novel target for reducing transmission of schistosomiasis.
title_short	Epigenetic changes modulate schistosome egg formation and are a novel target for reducing transmission of schistosomiasis.
title_full	Epigenetic changes modulate schistosome egg formation and are a novel target for reducing transmission of schistosomiasis.
title_fullStr	Epigenetic changes modulate schistosome egg formation and are a novel target for reducing transmission of schistosomiasis.
title_full_unstemmed	Epigenetic changes modulate schistosome egg formation and are a novel target for reducing transmission of schistosomiasis.
title_sort	epigenetic changes modulate schistosome egg formation and are a novel target for reducing transmission of schistosomiasis.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/510576f87bbf475a8b1ca3e4cd56c6a8
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Epigenetic changes modulate schistosome egg formation and are a novel target for reducing transmission of schistosomiasis.

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