Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA 16802, USA.
Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA.
Nucleic Acids Res. 2018 Sep 19;46(16):8385-8403. doi: 10.1093/nar/gky692.
The constitutive androstane receptor (CAR; NR1I3) is a nuclear receptor orchestrating complex roles in cell and systems biology. Species differences in CAR's effector pathways remain poorly understood, including its role in regulating liver tumor promotion. We developed transgenic mouse models to assess genome-wide binding of mouse and human CAR, following receptor activation in liver with direct ligands and with phenobarbital, an indirect CAR activator. Genomic interaction profiles were integrated with transcriptional and biological pathway analyses. Newly identified CAR target genes included Gdf15 and Foxo3, important regulators of the carcinogenic process. Approximately 1000 genes exhibited differential binding interactions between mouse and human CAR, including the proto-oncogenes, Myc and Ikbke, which demonstrated preferential binding by mouse CAR as well as mouse CAR-selective transcriptional enhancement. The ChIP-exo analyses also identified distinct binding motifs for the respective mouse and human receptors. Together, the results provide new insights into the important roles that CAR contributes as a key modulator of numerous signaling pathways in mammalian organisms, presenting a genomic context that specifies species variation in biological processes under CAR's control, including liver cell proliferation and tumor promotion.
组成型雄烷受体 (CAR; NR1I3) 是一种核受体，在细胞和系统生物学中起着复杂的作用。CAR 效应途径的种属差异仍知之甚少，包括其在调节肝肿瘤促进中的作用。我们开发了转基因小鼠模型，以评估直接配体和苯巴比妥（间接 CAR 激活剂）激活肝受体后，小鼠和人 CAR 的全基因组结合情况。基因组相互作用谱与转录和生物学途径分析进行了整合。新鉴定的 CAR 靶基因包括 Gdf15 和 Foxo3，它们是致癌过程的重要调节剂。大约 1000 个基因表现出小鼠和人 CAR 之间的差异结合相互作用，包括原癌基因 Myc 和 Ikbke，它们表现出小鼠 CAR 的优先结合以及小鼠 CAR 选择性转录增强。ChIP-exo 分析还为相应的小鼠和人受体确定了独特的结合基序。总之，这些结果为 CAR 作为众多信号通路在哺乳动物中的关键调节剂所起的重要作用提供了新的见解，提出了一个基因组背景，说明了 CAR 控制下的生物学过程的种属差异，包括肝细胞增殖和肿瘤促进。
