Identifying and validating the presence of Guanine-Quadruplexes (G4) within the blood fluke parasite Schistosoma mansoni.
Identifying and validating the presence of Guanine-Quadruplexes (G4) within the blood fluke parasite Schistosoma mansoni.
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鉴定和验证曼氏血吸虫血吸虫体内鸟嘌呤四链(G4)的存在。
DOI：
10.1371/journal.pntd.0008770
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发表时间：
2021-03
影响因子：
3.8
通讯作者：
Hoffmann KF
中科院分区：
文献类型：
--
作者：
Craven HM;Bonsignore R;Lenis V;Santi N;Berrar D;Swain M;Whiteland H;Casini A;Hoffmann KF
血吸虫病是一种被忽视的热带疾病，目前影响着全世界2.5亿多人。在缺乏免疫预防性疫苗和认识到吡喹酮单化疗控制血吸虫病有局限性的情况下，迫切需要新的战略来管理疾病负担。更好地了解染色体生物学可以确定以前没有记录的领域适合开发新的干预措施。在这里，我们第一次详细介绍了G-四链体（G4）和推定的四链体形成序列（PQS）内的曼氏血吸虫基因组的存在。我们发现，G4存在于基因内和基因间区域的7个常染色体以及性别定义的异源染色体对。在基因内区域中，G4特别富集在3 ′ UTR区域中。基因本体（GO）术语分析证明在wnt信号传导途径中显著的G4富集（p<0.05），并且如通过圆二色性（CD）光谱所阐明的，合成衍生自wnt相关基因的PQS寡核苷酸解析成平行和反平行G4基序。最后，利用单链抗G4抗体称为BG 4，我们确认在原位存在的G4内的成年女性和男性蠕虫的核。这些结果共同表明，G4靶向化合物可以作为新型驱虫剂进行测试，并强调了G4稳定分子可以作为治疗血吸虫病的候选药物的可能性。曼氏血吸虫引起血吸虫病，这是一种寄生虫病，影响着生活在发展中国家资源匮乏地区的数百万人。没有疫苗存在，目前的药物治疗有局限性，特别是对寄生虫的幼虫阶段无效。因此，需要新的药物来可持续地控制血吸虫病。对寄生虫生物学的进一步了解将发现新的靶点，并导致新疗法的发展。在这里，我们确定了G-四链体（G4）在S。mansoni G4是四链DNA结构，可以影响基因功能，迄今为止，尚未在任何寄生蠕虫中发现。计算分析预测了S. mansoni基因组，其中几个通过圆二色性光谱确认折叠。G4蛋白编码基因的分析发现，富集内的WNT信号通路，轴向发展的寄生虫的发展途径至关重要。此外，可以使用荧光抗体在蠕虫中检测G4，该荧光抗体选择性地识别核酸中的四链体结构。这项研究描述了寄生虫内一种以前未知的结构的存在，这可能为开发新的治疗方法提供了新的靶点。
Schistosomiasis is a neglected tropical disease that currently affects over 250 million individuals worldwide. In the absence of an immunoprophylactic vaccine and the recognition that mono-chemotherapeutic control of schistosomiasis by praziquantel has limitations, new strategies for managing disease burden are urgently needed. A better understanding of schistosome biology could identify previously undocumented areas suitable for the development of novel interventions. Here, for the first time, we detail the presence of G-quadruplexes (G4) and putative quadruplex forming sequences (PQS) within the Schistosoma mansoni genome. We find that G4 are present in both intragenic and intergenic regions of the seven autosomes as well as the sex-defining allosome pair. Amongst intragenic regions, G4 are particularly enriched in 3´ UTR regions. Gene Ontology (GO) term analysis evidenced significant G4 enrichment in the wnt signalling pathway (p<0.05) and PQS oligonucleotides synthetically derived from wnt-related genes resolve into parallel and anti-parallel G4 motifs as elucidated by circular dichroism (CD) spectroscopy. Finally, utilising a single chain anti-G4 antibody called BG4, we confirm the in situ presence of G4 within both adult female and male worm nuclei. These results collectively suggest that G4-targeted compounds could be tested as novel anthelmintic agents and highlights the possibility that G4-stabilizing molecules could be progressed as candidates for the treatment of schistosomiasis. Schistosoma mansoni causes schistosomiasis, a parasitic disease that affects millions of people living in resource-deprived areas of developing countries. No vaccine exists and the current drug treatment has limitations, notably inefficacy against the larval stages of the parasite. New drugs are, therefore, needed to sustainably control schistosomiasis. A further understanding of parasite biology will uncover new targets and lead to the development of novel therapies. Here, we identify the presence of G-Quadruplexes (G4s) in S. mansoni. G4s are four-stranded DNA structures that can affect gene function and, to date, have not been previously found in any parasitic helminth. Computational analysis predicted potential G4 folding sequences within the S. mansoni genome, several of which were confirmed to fold by circular dichroism spectroscopy. Analysis of G4-containing protein coding genes found an enrichment within the wnt signalling pathway, a developmental pathway crucial for axial development in the parasite. Additionally, G4s could be detected within adult worms using a fluorescent antibody that selectively recognises quadruplex structures in nucleic acids. This research describes the presence of a previously unknown structure within the parasite, which could present a new target for developing novel treatments.
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影响因子：
14.9
作者：
Gomez, D;Lemarteleur, T;Riou, JF
通讯作者：
Riou, JF
影响因子：
6.7
作者：
Harris LM;Merrick CJ
通讯作者：
Merrick CJ
DOI：
10.3390/molecules181012368
发表时间：
2013-10-08
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Bidzinska J;Cimino-Reale G;Zaffaroni N;Folini M
通讯作者：
Folini M
影响因子：
46.9
作者：
Chambers, Vicki S.;Marsico, Giovanni;Balasubramanian, Shankar
通讯作者：
Balasubramanian, Shankar
影响因子：
4.4
作者：
Gage, Hunter L.;Merrick, Catherine J.
通讯作者：
Merrick, Catherine J.