In vivo genome-wide binding interactions of mouse and human constitutive androstane receptors reveal novel gene targets
In vivo genome-wide binding interactions of mouse and human constitutive androstane receptors reveal novel gene targets
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DOI：
10.1093/nar/gky692
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发表时间：
2018-09-19
影响因子：
14.9
通讯作者：
Omiecinski, Curtis J.
中科院分区：
文献类型：
--
作者：
Niu, Ben;Coslo, Denise M.;Omiecinski, Curtis J.
结构性雄烷受体(CAR；NR1I3)是一种核受体，在细胞和系统生物学中发挥着复杂的作用。CAR效应器通路的物种差异仍然知之甚少，包括它在调节肝脏肿瘤促进中的作用。我们开发了转基因小鼠模型来评估小鼠和人类CAR的全基因组结合，随后用直接配体和间接CAR激活剂苯巴比妥激活肝脏中的受体。基因组相互作用图谱与转录和生物途径分析相结合。新发现的CAR靶基因包括GDF15和Foxo3，它们是致癌过程的重要调节因子。大约有1000个基因在小鼠和人CAR之间表现出不同的结合作用，包括原癌基因Myc和IKBKE，它们显示出与小鼠CAR的优先结合以及小鼠CAR选择性转录增强。CHIP-EXO分析还确定了小鼠和人类各自受体的不同结合基序。总之，这些结果为CAR作为哺乳动物体内众多信号通路的关键调节器所发挥的重要作用提供了新的见解，提供了一个基因组环境，指定了CAR控制下的生物过程中的物种变异，包括肝细胞增殖和肿瘤促进。
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.