Callegaro Giulia, Schimming Johannes P, Piñero González Janet, Kunnen Steven J, Wijaya Lukas, Trairatphisan Panuwat, van den Berk Linda, Beetsma Kim, Furlong Laura I, Sutherland Jeffrey J, Mollon Jennifer, Stevens James L, van de Water Bob
Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, the Netherlands.
Hospital del Mar Research Institute (IMIM), Pompeu Fabra University (UPF), Barcelona, Spain.
iScience. 2023 Jan 31;26(3):106094. doi: 10.1016/j.isci.2023.106094. eCollection 2023 Mar 17.
Animal testing is the current standard for drug and chemicals safety assessment, but hazards translation to human is uncertain. Human models can address the species translation but might not replicate complexity. Herein, we propose a network-based method addressing these translational multiscale problems that derives liver injury biomarkers applicable to human early safety screening. We applied weighted correlation network analysis (WGCNA) to a large rat liver transcriptomic dataset to obtain co-regulated gene clusters (modules). We identified modules statistically associated with liver pathologies, including a module enriched for ATF4-regulated genes as associated with the occurrence of hepatocellular single-cell necrosis, and as preserved in human liver models. Within the module, we identified TRIB3 and MTHFD2 as a novel candidate stress biomarkers, and developed and used BAC-eGFPHepG2 reporters in a compound screening, identifying compounds showing ATF4-dependent stress response and potential early safety signals.
动物实验是目前药物和化学品安全性评估的标准，但从动物到人类的危害转化存在不确定性。人体模型可以解决物种转化问题，但可能无法复制复杂性。在此，我们提出了一种基于网络的方法来解决这些跨尺度转化问题，该方法可得出适用于人类早期安全筛查的肝损伤生物标志物。我们将加权基因共表达网络分析（WGCNA）应用于一个大型大鼠肝脏转录组数据集，以获得共调控基因簇（模块）。我们确定了与肝脏病理在统计学上相关的模块，包括一个富含ATF4调控基因的模块，该模块与肝细胞单细胞坏死的发生相关，并且在人类肝脏模型中也存在。在该模块中，我们将TRIB3和MTHFD2鉴定为新型候选应激生物标志物，并在化合物筛选中开发并使用BAC-eGFPHepG2报告基因，鉴定出显示ATF4依赖性应激反应和潜在早期安全信号的化合物。
