The anti-fecundity effect of 5-azacytidine (5-AzaC) on Schistosoma mansoni is linked to dis-regulated transcription, translation and stem cell activities
|Author(s)||Geyer Kathrin K.1, Munshi Sabrina E.1, Vickers Martin2, Squance Michael1, Wilkinson Toby J.3, Berrar Daniel4, Chaparro Cristian5, Swain Martin T.1, Hoffmann Karl F.1|
|Affiliation(s)||1 : Aberystwyth Univ, IBERS, Edward Llwyd Bldg, Aberystwyth SY23 3DA, Dyfed, Wales.
2 : John Innes Ctr, Dept Cell & Dev Biol, Norwich Res Pk, Norwich NR4 7UH, Norfolk, England.
3 : Univ Edinburgh, Roslin Inst, Easter Bush Campus, Roslin EH25 9RG, Midlothian, Scotland.
4 : Tokyo Inst Technol, Data Sci Lab, Tokyo 1528550, Japan.
5 : Univ Perpignan Via Domitia, 58 Ave Paul Alduy,Bat R, F-66860 Perpignan, France.
|Source||International Journal For Parasitology-drugs And Drug Resistance (2211-3207) (Elsevier Sci Ltd), 2018-08 , Vol. 8 , N. 2 , P. 213-222|
|WOS© Times Cited||13|
|Keyword(s)||Schistosoma mansoni, Epigenetics, 5-Azacytidine, Fecundity, RNA-Seq, Protein synthesis, Stem cells|
|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 maleand 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.|