Toxicogenomic Analysis of Caenorhabditis elegans Reveals Genes Involved in the Resistance to Cadmium Toxicity

Exposure to cadmium is associated with a variety of human diseases. At low concentrations, cadmium activates the transcription of stress-responsive genes, which can prevent or repair the adverse effects caused by this metal. Using C. elegans, 290 genes were identified that are differentially expressed (1.5-fold) following a 4 or 24 hour exposure to cadmium. Several of these genes are known to be involved in metal detoxification, including mtl-1, mtl-2, cdr-1 and ttm-1, confirming the efficacy of the study. The majority, however, were not previously associated with metal-responsiveness and are novel. Gene Ontology analysis mapped these genes to cellular/ion trafficking, metabolic enzymes and proteolysis categories. RNAi-mediated inhibition of 50 cadmium-responsive genes resulted in an increased sensitivity to cadmium toxicity, demonstrating that these genes are involved in the resistance to cadmium toxicity. Several functional protein interacting networks were identified by interactome analysis. Within one network, the signaling protein KEL-8 was identified. Kel-8 protects C. elegans from cadmium toxicity in a mek-1 (MAPKK)-dependent manner. Because many C. elegans genes and signal transduction pathways are evolutionarily conserved, these results may contribute to the understanding of the functional roles of various genes in cadmium toxicity in higher organisms. Keywords: gene expression time course镉暴露与多种人类疾病密切相关。在低浓度条件下，镉可激活应激响应基因的转录，从而抵御或修复该金属引发的不良生理效应。本研究以秀丽隐杆线虫（C. elegans）为实验模型，对其进行4小时或24小时的镉暴露处理后，共鉴定出290个表达量差异达1.5倍及以上的基因。其中mtl-1、mtl-2、cdr-1与ttm-1等多个基因已被证实参与金属解毒过程，这一结果验证了本研究的可靠性。但绝大多数基因此前未被报道与金属响应相关，属于全新发现的镉响应基因。基因本体（Gene Ontology, GO）富集分析将这些基因注释至细胞/离子转运、代谢酶类及蛋白水解等功能类别中。通过RNA干扰（RNA interference, RNAi）技术抑制50个镉响应基因的表达后，秀丽隐杆线虫对镉毒性的敏感性显著升高，证实这些基因参与了镉毒性抗性机制。相互作用组（interactome）分析鉴定出多个功能性蛋白质相互作用网络，其中一个网络内包含信号蛋白KEL-8。KEL-8可通过依赖于mek-1（丝裂原活化蛋白激酶激酶，MAPKK）的信号通路，保护秀丽隐杆线虫免受镉毒性损伤。鉴于秀丽隐杆线虫的诸多基因与信号转导通路在进化上具有保守性，本研究结果有助于阐明高等生物中各类基因在镉毒性应答过程中的功能角色。关键词：基因表达时序分析