Xenobiotics and Loss of Cell Adhesion Drive Distinct Transcriptional Outcomes by Aryl Hydrocarbon Receptor Signaling
Xenobiotics and Loss of Cell Adhesion Drive Distinct Transcriptional Outcomes by Aryl Hydrocarbon Receptor Signaling
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DOI：
10.1124/mol.112.078873
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发表时间：
2012-12-01
影响因子：
3.6
通讯作者：
Whitelaw, Murray L.
中科院分区：
文献类型：
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作者：
Hao, Nan;Lee, Kian Leong;Whitelaw, Murray L.
芳香烃受体(AhR)是一种信号调节转录因子，在外源物质的直接结合下被激活。此外，将细胞从贴壁培养切换到悬浮培养也会激活AhR，这代表了AhR信号的非异种、生理性激活。在这里，我们发现AhR在配体[isopropyl-2-(1，3-dithietane-2-ylidene)-2-[N-(4-methylthiazol-2-yl)carbamoyl]acetate(YH439)处理的细胞和悬浮细胞中都被招募到靶基因增强子，这表明在这两条AhR激活的途径中有一个共同的靶基因诱导机制。然而，外源和悬浮激活的AhR信号之间的基因表达谱有很大的不同。POR和CldND1主要受配基处理的调节，而ApoER2和GANC则主要受悬浮条件的调节。经典的异源代谢AhR靶点，如Cyp1a1、CyP1B1和NQO1，都受到配体和悬浮条件的调节。AhR靶基因的时间表达模式也被发现是不同的，例如瞬时激活、瞬时抑制或持续表达变化。此外，序列分析结合染色质免疫沉淀分析和报告基因分析，在小鼠Tiparp基因的内含子1中发现了一个功能性的外源反应元件(XRE)，它在缺氧时也与缺氧诱导因子-1α结合，并具有四个XRE核心(GCGTG)的串联。我们的数据表明，在配体或悬浮诱导的AhR激活后，这个XRE串联位点同时调节Tiparp基因及其顺式反义非编码RNA的表达。这项工作为AhR信号如何通过配体和悬浮激活模式驱动不同的转录程序提供了新的见解。
The aryl hydrocarbon receptor (AhR) is a signal-regulated transcription factor, which is canonically activated by the direct binding of xenobiotics. In addition, switching cells from adherent to suspension culture also activates the AhR, representing a nonxenobiotic, physiological activation of AhR signaling. Here, we show that the AhR is recruited to target gene enhancers in both ligand [isopropyl-2-(1,3-dithietane-2-ylidene)-2-[N-(4-methylthiazol-2-yl)carbamoyl]acetate (YH439)]-treated and suspension cells, suggesting a common mechanism of target gene induction between these two routes of AhR activation. However, gene expression profiles critically differ between xenobiotic-and suspension-activated AhR signaling. Por and Cldnd1 were regulated predominantly by ligand treatments, whereas, in contrast, ApoER2 and Ganc were regulated predominantly by the suspension condition. Classic xenobiotic-metabolizing AhR targets such as Cyp1a1, Cyp1b1, and Nqo1 were regulated by both ligand and suspension conditions. Temporal expression patterns of AhR target genes were also found to vary, with examples of transient activation, transient repression, or sustained alterations in expression. Furthermore, sequence analysis coupled with chromatin immunoprecipitation assays and reporter gene analysis identified a functional xenobiotic response element (XRE) in the intron 1 of the mouse Tiparp gene, which was also bound by hypoxia-inducible factor-1 alpha during hypoxia and features a concatemer of four XRE cores (GCGTG). Our data suggest that this XRE concatemer site concurrently regulates the expression of both the Tiparp gene and its cis antisense noncoding RNA after ligand-or suspension-induced AhR activation. This work provides novel insights into how AhR signaling drives different transcriptional programs via the ligand versus suspension modes of activation.