The anti-fecundity effect of 5-azacytidine (5-AzaC) on Schistosoma mansoni is linked to dis-regulated transcription, translation and stem cell activities.

Autor:	Geyer KK; Institute of Biological, Environmental and Rural Sciences (IBERS), Edward Llwyd Building, Aberystwyth University, Aberystwyth SY23 3DA, United Kingdom. Electronic address: kkg6@aber.ac.uk., Munshi SE; Institute of Biological, Environmental and Rural Sciences (IBERS), Edward Llwyd Building, Aberystwyth University, Aberystwyth SY23 3DA, United Kingdom. Electronic address: sabrina.munshi@hotmail.co.uk., Vickers M; Department of Cell and Developmental Biology, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, United Kingdom. Electronic address: martinj.vickers@gmail.com., Squance M; Institute of Biological, Environmental and Rural Sciences (IBERS), Edward Llwyd Building, Aberystwyth University, Aberystwyth SY23 3DA, United Kingdom. Electronic address: michaels@terravesta.com., Wilkinson TJ; The Roslin Institute, The University of Edinburgh, Easter Bush Campus, Midlothian EH25 9RG, United Kingdom. Electronic address: toby.wilkinson@ed.ac.uk., Berrar D; Data Science Laboratory, Tokyo Institute of Technology, Tokyo 152-8550, Japan. Electronic address: daniel.berrar@ict.e.titech.ac.jp., Chaparro C; University of Perpignan Via Domitia, 58 Avenue Paul Alduy, Bat R, F-66860 Perpignan Cedex, France. Electronic address: Cristian.chaparro@univ-perp.fr., Swain MT; Institute of Biological, Environmental and Rural Sciences (IBERS), Edward Llwyd Building, Aberystwyth University, Aberystwyth SY23 3DA, United Kingdom. Electronic address: mts11@aber.ac.uk., Hoffmann KF; Institute of Biological, Environmental and Rural Sciences (IBERS), Edward Llwyd Building, Aberystwyth University, Aberystwyth SY23 3DA, United Kingdom. Electronic address: krh@aber.ac.uk.
Jazyk:	angličtina
Zdroj:	International journal for parasitology. Drugs and drug resistance [Int J Parasitol Drugs Drug Resist] 2018 Aug; Vol. 8 (2), pp. 213-222. Date of Electronic Publication: 2018 Apr 01.
DOI:	10.1016/j.ijpddr.2018.03.006
Abstrakt:	Uncontrolled host immunological reactions directed against tissue-trapped eggs precipitate a potentially lethal, pathological cascade responsible for schistosomiasis. Blocking schistosome egg production, therefore, presents a strategy for simultaneously reducing immunopathology as well as limiting disease transmission in endemic or emerging areas. We recently demonstrated that the ribonucleoside analogue 5-azacytidine (5-AzaC) inhibited Schistosoma mansoni oviposition, egg maturation and ovarian development. While these anti-fecundity effects were associated with a loss of DNA methylation, other molecular processes affected by 5-AzaC were not examined at the time. By comparing the transcriptomes of 5-AzaC-treated females to controls, we provide evidence that this ribonucleoside analogue also modulates other crucial aspects of schistosome egg-laying biology. For example, S. mansoni gene products associated with amino acid-, carbohydrate-, fatty acid-, nucleotide- and tricarboxylic acid (TCA)- homeostasis are all dysregulated in 5-AzaC treated females. To validate the metabolic pathway most significantly affected by 5-AzaC, amino acid metabolism, nascent protein synthesis was subsequently quantified in adult schistosomes. Here, 5-AzaC inhibited this process by 68% ±16.7% (SEM) in male- and 81% ±4.8% (SEM) in female-schistosomes. Furthermore, the transcriptome data indicated that adult female stem cells were also affected by 5-AzaC. For instance, 40% of transcripts associated with proliferating schistosome cells were significantly down-regulated by 5-AzaC. This finding correlated with a considerable reduction (95%) in the number of 5-ethynyl-2'-deoxyuridine (EdU) positive cells found in 5-AzaC-treated females. In addition to protein coding genes, the effect that 5-AzaC had on repetitive element expression was also assessed. Here, 46 repeats were found differentially transcribed between 5-AzaC-treated and control females with long terminal repeat (LTR) and DNA transposon classes being amongst the most significant. This study demonstrates that the anti-fecundity activity of 5-AzaC affects more than just DNA methylation in schistosome parasites. Further characterisation of these processes may reveal novel targets for schistosomiasis control. (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze:	MEDLINE
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