The anti-fecundity effect of 5-azacytidine (5-AzaC) on Schistosoma mansoni is linked to dis-regulated transcription, translation and stem cell activities.
The anti-fecundity effect of 5-azacytidine (5-AzaC) on Schistosoma mansoni is linked to dis-regulated transcription, translation and stem cell activities.
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DOI：
10.1016/j.ijpddr.2018.03.006
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发表时间：
2018-08
期刊：
影响因子：
--
通讯作者：
Hoffmann KF
中科院分区：
文献类型：
--
作者：
Geyer KK;Munshi SE;Vickers M;Squance M;Wilkinson TJ;Berrar D;Chaparro C;Swain MT;Hoffmann KF
不受控制的宿主免疫反应针对组织捕获的卵沉淀一个潜在的致命的，病理级联负责血吸虫病。因此，阻断寄生虫卵的产生是一种同时减少免疫病理学和限制流行或新兴地区疾病传播的策略。我们最近发现，核糖核苷类似物5-氮杂胞苷（5-AzaC）抑制曼氏血吸虫产卵，卵成熟和卵巢发育。虽然这些抗生育作用与DNA甲基化的丧失有关，但当时没有检查受5-AzaC影响的其他分子过程。通过比较5-AzaC处理的女性对照组的转录组，我们提供的证据表明，这种核糖核苷类似物也调节其他关键方面的产卵生物学。例如，S.与氨基酸-、碳水化合物-、脂肪酸-、核苷酸-和三羧酸（TCA）-稳态相关的mansoni基因产物在5-AzaC处理的雌性中均失调。为了验证受5-AzaC最显著影响的代谢途径，随后在成体染色体中定量氨基酸代谢、新生蛋白质合成。在这里，5-AzaC在雄性和雌性染色体中分别抑制了68% ±16.7%（SEM）和81% ±4.8%（SEM）的这一过程。此外，转录组数据表明，成年女性干细胞也受到5-AzaC的影响。例如，40%的转录本与增殖的溶酶体细胞显着下调5-AzaC。这一发现与5-AzaC处理雌性动物中发现的5-乙炔基-2 ′-脱氧尿苷（EdU）阳性细胞数量显著减少（95%）相关。除了蛋白质编码基因外，还评估了5-AzaC对重复元件表达的影响。在这里，发现46个重复之间的5-氮杂丙啶治疗和控制女性的长末端重复序列（LTR）和DNA转座子类是最显着的差异转录。这项研究表明，5-AzaC的抗生殖活性影响的不仅仅是DNA甲基化的寄生虫。这些过程的进一步表征可能揭示血吸虫病控制的新目标。核糖核苷5-氮杂胞苷（5-AzaC）抑制精子卵的产生。5-AzaC调节核糖体的转录和翻译。血吸虫干细胞增殖和维持受5-AzaC影响。
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. The ribonucleoside 5-azacytidine (5-AzaC) inhibits schistosome egg production. 5-AzaC modulates schistosome transcription and translation. Schistosome stem cell proliferation and maintenance are affected by 5-AzaC.
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影响因子：
14.9
作者：
Caspi R;Billington R;Ferrer L;Foerster H;Fulcher CA;Keseler IM;Kothari A;Krummenacker M;Latendresse M;Mueller LA;Ong Q;Paley S;Subhraveti P;Weaver DS;Karp PD
通讯作者：
Karp PD
影响因子：
1.5
作者：
Howe KL;Bolt BJ;Shafie M;Kersey P;Berriman M
通讯作者：
Berriman M
影响因子：
9.6
作者：
Cosseau C;Wolkenhauer O;Padalino G;Geyer KK;Hoffmann KF;Grunau C
通讯作者：
Grunau C
影响因子：
16.6
作者：
通讯作者：
--
影响因子：
4.4
作者：
Criscione SW;Zhang Y;Thompson W;Sedivy JM;Neretti N
通讯作者：
Neretti N