Zheng Pai, Kang Yulin, Han Shuo, Feng Huimin, Ha Feizai, Long Changmao, Zhou Di, Hu Guiping, Chen Zhangjian, Wang Zengmiao, Wang Tiancheng, Jia Guang
Department of Occupational and Environmental Health Science, School of Public Health, Peking University, Beijing, China.
Institute of Environmental Information, Chinese Research Academy of Environmental Sciences, Beijing, China.
Front Genet. 2021 Jan 13;11:597803. doi: 10.3389/fgene.2020.597803. eCollection 2020.
Hexavalent chromium [Cr(VI)] is a well-known occupational carcinogen, but the mechanisms contributing to DNA damage and cell cycle alternation have not been fully characterized. To study the dose-response effects of Cr(VI) on transcription, we exposed BEAS-2B cells to Cr(VI) at concentrations of 0.2, 0.6, and 1.8 μmol/L for 24 h. Here, we identified 1,484 differentially expressed genes (DEGs) in our transcript profiling data, with the majority of differentially expressed transcripts being downregulated. Our results also showed that these DEGs were enriched in pathways associated with the cell cycle, including DNA replication, chromatin assembly, and DNA repair. Using the differential expressed genes related to cell cycle, a weighted gene co-expression network was constructed and a key mRNA-lncRNA regulation module was identified under a scale-free network with topological properties. Additionally, key driver analysis (KDA) was applied to the mRNA-lncRNA regulation module to identify the driver genes. The KDA revealed that ARD3 (FDR = 1.46 × 10), SND1 (FDR = 5.24 × 10), and lnc-DHX32-2:1 (FDR = 1.43 × 10) were particularly highlighted in the category of G2/M, G1/S, and M phases. Moreover, several genes we identified exhibited great connectivity in our causal gene network with every key driver gene, including CDK14, POLA1, lnc-NCS1-2:1, and lnc-FOXK1-4:1 (all FDR < 0.05 in those phases). Together, these results obtained using mathematical approaches and bioinformatics algorithmics might provide potential new mechanisms involved in the cytotoxicity induced by Cr.
六价铬[Cr(VI)]是一种著名的职业致癌物，但其导致DNA损伤和细胞周期改变的机制尚未完全明确。为了研究Cr(VI)对转录的剂量反应效应，我们将BEAS-2B细胞暴露于浓度为0.2、0.6和1.8 μmol/L的Cr(VI)中24小时。在此，我们在转录谱数据中鉴定出1484个差异表达基因(DEGs)，其中大多数差异表达转录本被下调。我们的结果还表明，这些DEGs在与细胞周期相关的途径中富集，包括DNA复制、染色质组装和DNA修复。利用与细胞周期相关的差异表达基因，构建了加权基因共表达网络，并在具有拓扑性质的无标度网络下鉴定出一个关键的mRNA-lncRNA调控模块。此外，对mRNA-lncRNA调控模块应用关键驱动因子分析(KDA)来鉴定驱动基因。KDA显示，ARD3（FDR = 1.46 × 10）、SND1（FDR = 5.24 × 10）和lnc-DHX32-2:1（FDR = 1.43 × 10）在G2/M、G1/S和M期类别中尤为突出。此外，我们鉴定出的几个基因在我们的因果基因网络中与每个关键驱动基因都表现出很强的连通性，包括CDK14、POLA1、lnc-NCS1-2:1和lnc-FOXK1-4:1（在这些阶段所有FDR均< 0.05）。总之，这些使用数学方法和生物信息学算法获得的结果可能为Cr诱导的细胞毒性提供潜在的新机制。
