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

Kathrin Geyer, Sabrina E. Munshi, Martin Vickers, Michael Squance, Toby Wilkinson, Daniel Berrar, Cristian Chaparro, Martin Swain, Karl Hoffmann

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Abstract

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
Original languageEnglish
Pages (from-to)213-222
Number of pages10
JournalInternational Journal for Parasitology: Drugs and Drug Resistance
Volume8
Issue number2
Early online date01 Apr 2018
DOIs
Publication statusPublished - 01 Aug 2018

Keywords

  • 5-Azacytidine
  • Epigenetics
  • Fecundity
  • Protein synthesis
  • RNA-Seq
  • Schistosoma mansoni
  • Stem cells
  • Transcriptome
  • Citric Acid Cycle/drug effects
  • Gene Expression Profiling
  • Schistosoma mansoni/cytology
  • Terminal Repeat Sequences/genetics
  • Animals
  • Sequence Analysis, RNA
  • Stem Cells/drug effects
  • DNA Methylation/drug effects
  • Female
  • Azacitidine/pharmacology
  • Fertility/drug effects
  • Gene Expression Regulation/drug effects
  • Schistosomiasis mansoni/parasitology

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