RNA-Seq reveals common and unique PXR- and CAR-target gene signatures in the mouse liver transcriptome.
RNA-Seq reveals common and unique PXR- and CAR-target gene signatures in the mouse liver transcriptome.
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DOI：
10.1016/j.bbagrm.2016.04.010
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发表时间：
2016-09
期刊：
影响因子：
--
通讯作者：
Klaassen CD
中科院分区：
文献类型：
--
作者：
Cui JY;Klaassen CD
孕烷X受体（PXR）和组成型雄烷受体（CAR）是众所周知的具有重叠功能的外源感应核受体。然而，缺乏定量表征来区分PXR和CAR在肝脏中的靶基因和信号通路。本研究使用RNA-Seq技术对成年野生型小鼠肝脏中的PXR靶点和CAR靶点进行了转录组学比较，这些小鼠分别接受了典型PXR配体PCN （200 mg/kg，每日1次，玉米油中4天）或典型CAR配体TCPOBOP （3 mg/kg，每日1次，玉米油中4天）治疗。在给定剂量下，TCPOBOP差异调节的基因（2125个）比PCN（212个）多得多，并且147个相同的基因被两种化学物质差异调节。正如预期的那样，PCN和TCPOBOP不同调控的顶端通路都参与了外源代谢，它们也上调了类视黄醇代谢相关基因，但下调了炎症和铁稳态相关基因。就独特的途径而言，PXR激活似乎与芳烃受体信号通路重叠，而CAR激活似乎与farnesoid X受体信号通路、急性期反应和线粒体功能障碍重叠。差异调节药物加工基因（DPGs）的mrna分为三种模式，即tcpobop诱导的、pcn诱导的和tcpobop抑制的基因簇。PCN和tcpoboop均上调了差异调节药物加工基因（DPGs）、i期和ii期酶以及外排转运蛋白的累积mrna，而TCPOBOP仅下调了摄取转运蛋白的累积mrna。在对照和受体激活条件下，检测每个DPG类别的绝对mRNA丰度，以预测特定DPG基因在PXR/ car介导的药代动力学反应中的贡献。TCPOBOP在整个肝脏转录组中较好的差异调控与许多DNA和组蛋白表观遗传修饰子表达的显著变化相关。总之，本研究揭示了PXR和CAR在小鼠肝脏中使用其原型配体进行药理激活后已知的和新颖的，以及共同的和独特的靶点。本研究的结果将进一步支持这些受体在调节肝脏外源代谢和中间代谢的稳态中的作用，并有助于区分PXR和CAR信号在各种生理和病理生理条件下的作用。
The pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are well-known xenobiotic-sensing nuclear receptors with overlapping functions. However, there lacks a quantitative characterization to distinguish between the PXR and CAR target genes and signaling pathways in liver. The present study performed a transcriptomic comparison of the PXR- and CAR-targets using RNA-Seq in livers of adult wild-type mice that were treated with the prototypical PXR ligand PCN (200 mg/kg, i.p. once daily for 4 days in corn oil) or the prototypical CAR ligand TCPOBOP (3 mg/kg, i.p., once daily for 4 days in corn oil). At the given doses, TCPOBOP differentially regulated many more genes (2125) than PCN (212), and 147 of the same genes were differentially regulated by both chemicals. As expected, the top pathways differentially regulated by both PCN and TCPOBOP were involved in xenobiotic metabolism, and they also up-regulated genes involved in retinoid metabolism, but down-regulated genes involved in inflammation and iron homeostasis. Regarding unique pathways, PXR activation appeared to overlap with the aryl hydrocarbon receptor signaling, whereas CAR activation appeared to overlap with the farnesoid X receptor signaling, acute-phase response, and mitochondrial dysfunction. The mRNAs of differentially regulated drug-processing genes (DPGs) partitioned into three patterns, namely TCPOBOP-induced, PCN-induced, as well as TCPOBOP-suppressed gene clusters. The cumulative mRNAs of the differentially regulated drug-processing genes (DPGs), phase-I and –II enzymes, as well as efflux transporters were all up-regulated by both PCN and TCPOBOPOP, whereas the cumulative mRNAs of the uptake transporters were down-regulated only by TCPOBOP. The absolute mRNA abundance in control and receptor-activated conditions was examined in each DPG category to predict the contribution of specific DPG genes in the PXR/CAR-mediated pharmacokinetic responses. The preferable differential regulation by TCPOBOP in the entire hepatic transcriptome correlated with a marked change in the expression of many DNA and histone epigenetic modifiers. In conclusion, the present study has revealed known and novel, as well as common and unique targets of PXR and CAR in mouse liver following pharmacological activation using their prototypical ligands. Results from this study will further support the role of these receptors in regulating the homeostasis of xenobiotic and intermediary metabolism in liver, and aid in distinguishing between PXR and CAR signaling at various physiological and pathophysiological conditions.
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影响因子：
14.9
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