Institute of Cytology and Genetics, 630090 Novosibirsk, Russia.
Faculty of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russia.
Int J Mol Sci. 2020 Oct 23;21(21):7858. doi: 10.3390/ijms21217858.
Dioxins are one of the most potent anthropogenic poisons, causing systemic disorders in embryonic development and pathologies in adults. The mechanism of dioxin action requires an aryl hydrocarbon receptor (AhR), but the downstream mechanisms are not yet precisely clear. Here, we performed a meta-analysis of all available transcriptome datasets taken from human cell cultures exposed to 2,3,7,8-tetrachlorodibenzo--dioxin (TCDD). Differentially expressed genes from different experiments overlapped partially, but there were a number of those genes that were systematically affected by TCDD. Some of them have been linked to toxic dioxin effects, but we also identified other attractive targets. Among the genes that were affected by TCDD, there are functionally related gene groups that suggest an interplay between retinoic acid, AhR, and Wnt signaling pathways. Next, we analyzed the upstream regions of differentially expressed genes and identified potential transcription factor (TF) binding sites overrepresented in the genes responding to TCDD. Intriguingly, the dioxin-responsive element (DRE), the binding site of AhR, was not overrepresented as much as other cis-elements were. Bioinformatics analysis of the AhR binding profile unveils potential cooperation of AhR with E2F2, CTCFL, and ZBT14 TFs in the dioxin response. We discuss the potential implication of these predictions for further dioxin studies.
二恶英是最具毒性的人为毒物之一，会导致胚胎发育的全身紊乱和成人的病理变化。二恶英的作用机制需要芳烃受体 (AhR)，但其下游机制尚不完全清楚。在这里，我们对所有已发表的人类细胞培养物暴露于 2,3,7,8-四氯二苯并对二恶英 (TCDD) 的转录组数据集进行了荟萃分析。来自不同实验的差异表达基因部分重叠，但有许多基因受到 TCDD 的系统影响。其中一些基因与有毒的二恶英效应有关，但我们也确定了其他有吸引力的靶标。在受 TCDD 影响的基因中，存在功能相关的基因群，表明视黄酸、AhR 和 Wnt 信号通路之间存在相互作用。接下来，我们分析了差异表达基因的上游区域，并确定了对 TCDD 反应的基因中存在的潜在转录因子 (TF) 结合位点。有趣的是，二恶英反应元件 (DRE)，即 AhR 的结合位点，并没有像其他顺式元件那样被过度代表。差异表达基因的 AhR 结合谱的生物信息学分析揭示了 AhR 与 E2F2、CTCFL 和 ZBT14 TF 在二恶英反应中的潜在合作。我们讨论了这些预测对进一步的二恶英研究的潜在意义。
