Gene co-regulation and co-expression in the aryl hydrocarbon receptor-mediated transcriptional regulatory network in the mouse liver
Gene co-regulation and co-expression in the aryl hydrocarbon receptor-mediated transcriptional regulatory network in the mouse liver
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DOI：
10.1007/s00204-019-02620-5
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发表时间：
2020-01-01
影响因子：
6.1
通讯作者：
Bhattacharya, Sudin
中科院分区：
文献类型：
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作者：
Josyula, Navya;Andersen, Melvin E.;Bhattacharya, Sudin
芳烃受体(AHR)是由持久性环境污染物2，3，7，8-四氯二苯并-对二恶英(TCDD)激活的一种配体诱导的转录因子，在发现40年后，它仍然是一个具有内源性作用的谜分子。在这里，我们已经组装了雌性C57BL/6小鼠口服30微克/公斤TCDD的AHR基因调控网络的全球图谱，该图谱来自先前发表的基因表达和全基因组TF结合数据集。利用Kohonen自组织映射和子空间聚类，我们发现AHR网络中共同上游转录因子共同调控的基因呈现出共同表达的模式。直接结合、间接结合和非基因组AHR靶基因表现出不同的表达模式，直接结合的靶基因与最高的中值表达相关。有趣的是，在直接结合的AHR靶基因中，表达水平随着近端启动子区域AHR结合部位的数量增加而增加。最后，我们证明了AHR网络中的共同调控基因激活了不同的下游生物过程组。尽管这里描述的具体发现仅限于短期TCDD暴露下的肝脏效应，但这项工作描述了一种普遍的方法来重建和分析潜在的细胞应激反应的转录调控级联，揭示了从最初的信号事件到表型结果的网络层次和信息流的性质。这种重建的网络可以形成新一代量化不良后果途径的基础。
Four decades after its discovery, the aryl hydrocarbon receptor (AHR), a ligand-inducible transcription factor (TF) activated by the persistent environmental contaminant 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), remains an enigmatic molecule with a controversial endogenous role. Here, we have assembled a global map of the AHR gene regulatory network in female C57BL/6 mice orally gavaged with 30 mu g/kg of TCDD from a combination of previously published gene expression and genome-wide TF-binding data sets. Using Kohonen self-organizing maps and subspace clustering, we show that genes co-regulated by common upstream TFs in the AHR network exhibit a pattern of co-expression. Directly bound, indirectly bound, and non-genomic AHR target genes exhibit distinct expression patterns, with the directly bound targets associated with highest median expression. Interestingly, among the directly bound AHR target genes, the expression level increases with the number of AHR-binding sites in the proximal promoter regions. Finally, we show that co-regulated genes in the AHR network activate distinct groups of downstream biological processes. Although the specific findings described here are restricted to hepatic effects under short-term TCDD exposure, this work describes a generalizable approach to the reconstruction and analysis of transcriptional regulatory cascades underlying cellular stress response, revealing network hierarchy and the nature of information flow from the initial signaling events to phenotypic outcomes. Such reconstructed networks can form the basis of a new generation of quantitative adverse outcome pathways.