Garrison P M, Rogers J M, Brackney W R, Denison M S
Department of Environmental Toxicology, Meyer Hall, One Shields Avenue, Davis, California 95616, USA.
Arch Biochem Biophys. 2000 Feb 15;374(2):161-71. doi: 10.1006/abbi.1999.1620.
The aromatic hydrocarbon receptor (AhR) is a ligand-dependent basic helix-loop-helix-PAS-containing transcription factor which is activated by chemicals such as 2,3,7,8-tetrachlorodibenzo-p-dioxin. Constitutive expression of the AhR gene occurs in a tissue- and developmentally specific manner and appears to be altered by chemicals which affect histone deacetylase (HDAC) activity in cells in culture. Here we have directly characterized the effects of two HDAC inhibitors, n-butyrate and trichostatin A, on the promoter activity of the murine AhR gene. HDAC inhibitors increased the constitutive activity of the AhR gene promoter in a luciferase reporter construct by five- to sevenfold in a dose- and time-dependent manner in several cell lines and was correlated with an increase in endogenous AhR activity in an AhR-deficient cell line. Deletion analysis of the upstream region of the AhR gene localized the HDAC inhibitor effect to a 167-bp region encompassing -77 to +90 of the AhR gene promoter. Cotransfection of an AhR promoter-luciferase reporter plasmid with a vector expressing the E1A(12s) oncoprotein, a negative regulator of p300, a protein with histone acetylase activity, decreased AhR promoter activity fivefold. Overall, our results support a role for histone acetylation in the transcriptional activity of the AhR gene promoter.
芳烃受体（AhR）是一种依赖配体的含碱性螺旋-环-螺旋-PAS结构域的转录因子，可被2,3,7,8-四氯二苯并对二恶英等化学物质激活。AhR基因的组成型表达以组织和发育特异性的方式发生，并且似乎会受到影响培养细胞中组蛋白去乙酰化酶（HDAC）活性的化学物质的改变。在此，我们直接表征了两种HDAC抑制剂丁酸盐和曲古抑菌素A对小鼠AhR基因启动子活性的影响。HDAC抑制剂在几种细胞系中以剂量和时间依赖性方式使荧光素酶报告基因构建体中AhR基因启动子的组成型活性增加了五至七倍，并且与AhR缺陷细胞系中内源性AhR活性的增加相关。对AhR基因上游区域的缺失分析将HDAC抑制剂的作用定位到一个167bp的区域，该区域涵盖AhR基因启动子的-77至+90。将AhR启动子-荧光素酶报告质粒与表达E1A（12s）癌蛋白（p300的负调节剂，一种具有组蛋白乙酰化酶活性的蛋白质）的载体共转染，可使AhR启动子活性降低五倍。总体而言，我们的结果支持组蛋白乙酰化在AhR基因启动子转录活性中的作用。
