Intronic DNA elements regulate Nrf2 chemical responsiveness of the human microsomal epoxide hydrolase gene (EPHX1) through a far upstream alternative promoter.
Intronic DNA elements regulate Nrf2 chemical responsiveness of the human microsomal epoxide hydrolase gene (EPHX1) through a far upstream alternative promoter.
复制标题
内含子 DNA 元件通过上游的替代启动子调节人微粒体环氧化物水解酶基因 (EPHX1) 的 Nrf2 化学反应性。
DOI：
10.1016/j.bbagrm.2014.03.014
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发表时间：
2014-06
影响因子：
4.7
通讯作者：
Omiecinski, Curtis J.
中科院分区：
文献类型：
--
作者：
Su, Shengzhong;Yang, Xi;Omiecinski, Curtis J.
在人类中，微粒体环氧化物水解酶（mEH）具有重要的生物学功能，是暴露于外来化学物质引起的解毒和生物激活命运的基础。先前，我们发现人类mEH基因转录是由替代启动子启动的。各自的转录本具有组织特异性，上游的E1b启动子主要促进mEH的表达。结果表明，暴露于Nrf2激活剂，萝卜硫素（SFN）和叔丁基对苯二酚（tBHQ），显著激活E1b转录在人肺和肝细胞。基因组分析发现，在E1b与下游E1启动子分离的约15 kb中间序列中，存在两个主要的dna酶I超敏区（HS-1和HS-2）。在BEAS-2B细胞中，Nrf2效应因子SFN和thbhq通过抗氧化反应元件（ARE）选择性激活了更远端的HS-2。在HS-2增强子中进一步鉴定了1/12- o - tetradecanoylpholl -13-acetate相互作用的激活蛋白，该蛋白还有助于re介导的E1b启动子的诱导反应性。结果表明，ARE调节与其他转录复合物结合，调节mEH的组织特异性表达，这些过程可能协调mEH活性在人体组织中的保护和生物活化功能。
In humans, microsomal epoxide hydrolase (mEH) contributes important biological functions that underlie both detoxification and bioactivation fates arising from exposures to foreign chemicals. Previously, we discovered that human mEH gene transcription is initiated from alternative promoters. The respective transcripts are programmed with tissue specificity and the upstream E1b promoter contributes predominantly to mEH expression. The results presented demonstrate that exposures to the Nrf2 activators, sulforaphane (SFN) and tert-butylhydroquinone (tBHQ), markedly activate E1b transcription in human lung and liver cells. Genomic analyses identified two major DNase I hypersensitive regions (HS-1 and HS-2) within the ~15 kb intervening sequence separating E1b from the downstream E1 promoter. In BEAS-2B cells, the Nrf2 effectors, SFN and tBHQ, selectively activated the more distal HS-2 through an antioxidant-response element (ARE). An activator protein 1/12-O-tetradecanoylphorbol-13-acetate interaction was further identified within the HS-2 enhancer that functioned to additionally contribute to ARE-mediated induction responsiveness of the E1b promoter. The results demonstrate that ARE modulation, integrated with additional transcriptional complexes, regulates the tissue-specific expression of mEH and that these processes likely coordinate both the protective and bioactivation functions contributed by mEH activities in human tissues.
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影响因子：
14.9
作者：
Chorley BN;Campbell MR;Wang X;Karaca M;Sambandan D;Bangura F;Xue P;Pi J;Kleeberger SR;Bell DA
通讯作者：
Bell DA
影响因子：
6
作者：
Ma, Qiang;Battelli, Lori;Hubbs, Ann F.
通讯作者：
Hubbs, Ann F.
影响因子：
4.8
作者：
Erickson, AM;Nevarea, Z;Mulcahy, RT
通讯作者：
Mulcahy, RT
影响因子：
11.2
作者：
Ohta, Tsutonm;Iijima, Kumiko;Hirohashi, Setsuo
通讯作者：
Hirohashi, Setsuo
影响因子：
3.8
作者：
Kwak MK;Kensler TW
通讯作者：
Kensler TW