Adaptive and specialised transcriptional responses to xenobiotic stress in Caenorhabditis elegans are regulated by nuclear hormone receptors.
Adaptive and specialised transcriptional responses to xenobiotic stress in Caenorhabditis elegans are regulated by nuclear hormone receptors.
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DOI：
10.1371/journal.pone.0069956
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Urwin PE
中科院分区：
文献类型：
--
作者：
Jones LM;Rayson SJ;Flemming AJ;Urwin PE
在靶生物和非靶生物中，外源生物代谢和排泄途径的表征对于合理设计有效和特异性的新型生物活性分子至关重要。因此，我们研究了模型线虫秀丽隐杆线虫对各种代表一系列假定作用模式的外源药物的诱导反应。在初步的微阵列分析中，特异性诱导的大多数基因编码了来自I期和II期代谢的酶，包括细胞色素p450、短链脱氢酶、udp -葡萄糖醛基转移酶和谷胱甘肽转移酶。通过定量PCR证实了基因表达的变化，并对12种诱导酶转录启动子驱动的报告菌株进行了GFP诱导研究。所诱导的代谢基因的特殊补体被发现高度依赖于所应用的异种生物。已知的对化学物质ahr-1、hif-1、mdt-15和nhr-8反应的调节因子在这些诱导反应中是不需要的，并且skn-1仅从两个启动子调节GFP的表达。报告菌株与系统RNAi筛选一起使用，以确定在外源暴露下驱动这些基因表达的转录因子。这些转录因子似乎调节特定的异种反应，在标准条件下没有报道的表型。以nhr-176为重点，我们证明了该转录因子在介导对噻苯达唑的抗性中的作用。
Characterisation of the pathways by which xenobiotics are metabolised and excreted in both target and non-target organisms is crucial for the rational design of effective and specific novel bioactive molecules. Consequently, we have investigated the induced responses of the model nematode Caenorhabditis elegans to a variety of xenobiotics which represent a range of putative modes of action. The majority of genes that were specifically induced in preliminary microarray analyses encoded enzymes from Phase I and II metabolism, including cytochrome P450s, short chain dehydrogenases, UDP-glucuronosyl transferases and glutathione transferases. Changes in gene expression were confirmed by quantitative PCR and GFP induction in reporter strains driven by promoters for transcription of twelve induced enzymes was investigated. The particular complement of metabolic genes induced was found to be highly contingent on the xenobiotic applied. The known regulators of responses to applied chemicals ahr-1, hif-1, mdt-15 and nhr-8 were not required for any of these inducible responses and skn-1 regulated GFP expression from only two of the promoters. Reporter strains were used in conjunction with systematic RNAi screens to identify transcription factors which drive expression of these genes under xenobiotic exposure. These transcription factors appeared to regulate specific xenobiotic responses and have no reported phenotypes under standard conditions. Focussing on nhr-176 we demonstrate the role of this transcription factor in mediating the resistance to thiabendazole.
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