Schulthess Pascal, Löffler Alexandra, Vetter Silvia, Kreft Luisa, Schwarz Michael, Braeuning Albert, Blüthgen Nils
Institute for Pathology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany Integrative Research Institute for the Life Sciences and Institute for Theoretical Biology, Humboldt University of Berlin, Philippstr. 13, 10115 Berlin, Germany.
Institute for Experimental and Clinical Pharmacology and Toxicology, Department of Toxicology, University of Tübingen, Wilhelmstraße 56, 72074 Tübingen, Germany.
Nucleic Acids Res. 2015 Jun 23;43(11):5318-30. doi: 10.1093/nar/gkv423. Epub 2015 May 1.
Genes involved in detoxification of foreign compounds exhibit complex spatiotemporal expression patterns in liver. Cytochrome P450 1A1 (CYP1A1), for example, is restricted to the pericentral region of liver lobules in response to the interplay between aryl hydrocarbon receptor (AhR) and Wnt/β-catenin signaling pathways. However, the mechanisms by which the two pathways orchestrate gene expression are still poorly understood. With the help of 29 mutant constructs of the human CYP1A1 promoter and a mathematical model that combines Wnt/β-catenin and AhR signaling with the statistical mechanics of the promoter, we systematically quantified the regulatory influence of different transcription factor binding sites on gene induction within the promoter. The model unveils how different binding sites cooperate and how they establish the promoter logic; it quantitatively predicts two-dimensional stimulus-response curves. Furthermore, it shows that crosstalk between Wnt/β-catenin and AhR signaling is crucial to understand the complex zonated expression patterns found in liver lobules. This study exemplifies how statistical mechanical modeling together with combinatorial reporter assays has the capacity to disentangle the promoter logic that establishes physiological gene expression patterns.
参与外源化合物解毒的基因在肝脏中呈现出复杂的时空表达模式。例如，细胞色素P450 1A1（CYP1A1）在芳烃受体（AhR）和Wnt/β-连环蛋白信号通路之间的相互作用下，局限于肝小叶的中央周围区域。然而，这两条信号通路协调基因表达的机制仍知之甚少。借助29种人类CYP1A1启动子的突变构建体以及一个将Wnt/β-连环蛋白和AhR信号与启动子的统计力学相结合的数学模型，我们系统地量化了不同转录因子结合位点对启动子内基因诱导的调控影响。该模型揭示了不同结合位点如何协同作用以及它们如何建立启动子逻辑；它定量预测了二维刺激-反应曲线。此外，研究表明Wnt/β-连环蛋白和AhR信号之间的相互作用对于理解肝小叶中复杂的分区表达模式至关重要。这项研究例证了统计力学建模与组合报告基因检测相结合如何有能力解析建立生理基因表达模式的启动子逻辑。
