Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner.
Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner.
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DOI：
10.1101/gr.135681.111
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发表时间：
2012-11
期刊：
影响因子：
7
通讯作者：
Myers RM
中科院分区：
文献类型：
--
作者：
Gertz J;Reddy TE;Varley KE;Garabedian MJ;Myers RM
体内合成的内源性雌激素通过激活不同类型细胞中的雌激素受体来影响基因调控。在儿童和成人的血液中也可以发现具有雌激素特性的外源性化合物。这些环境雌激素对基因调控的全基因组影响尚不清楚。为了在基因组水平上获得对环境和内源性雌激素反应的基因调控的综合观点，我们进行了CHIP-SEQ来确定雌激素受体1(ESR1；以前的雌激素受体α)结合部位，以及暴露于双酚A(BPA；在塑料中发现)、染料木素(GEN；在大豆中发现)或17β-雌二醇(E2；一种内源性雌激素)暴露的子宫内膜癌细胞中的RNA-SEQ。Gen和BPA处理诱导了数千个ESR1结合位点和>；50基因表达的变化，代表了E2诱导的基因调控变化的一个子集。受E2影响的基因高度富含核糖体相关蛋白；然而，Gen和BPA未能调节大多数核糖体相关蛋白，而是富含羧酸转运蛋白。基因表达的依赖于治疗的变化与治疗依赖的ESR1结合位点有关，除了许多被E2上调的基因含有BPA诱导的ESR1结合位点，但在BPA处理后没有表现出任何表达变化。在乳腺癌细胞系T-47D中，GEN和BPA与E2的关系相似，细胞类型特异性发挥的作用比治疗特异性大得多。总体而言，这两种环境雌激素都明确地通过ESR1在全基因组范围内调节基因表达，尽管与内源性雌激素E2相比，ESR1结合位点较少，基因表达变化较小。
Endogenous estrogens that are synthesized in the body impact gene regulation by activating estrogen receptors in diverse cell types. Exogenous compounds that have estrogenic properties can also be found circulating in the blood in both children and adults. The genome-wide impact of these environmental estrogens on gene regulation is unclear. To obtain an integrated view of gene regulation in response to environmental and endogenous estrogens on a genome-wide scale, we performed ChIP-seq to identify estrogen receptor 1 (ESR1; previously estrogen receptor α) binding sites, and RNA-seq in endometrial cancer cells exposed to bisphenol A (BPA; found in plastics), genistein (GEN; found in soybean), or 17β-estradiol (E2; an endogenous estrogen). GEN and BPA treatment induces thousands of ESR1 binding sites and >50 gene expression changes, representing a subset of E2-induced gene regulation changes. Genes affected by E2 were highly enriched for ribosome-associated proteins; however, GEN and BPA failed to regulate most ribosome-associated proteins and instead enriched for transporters of carboxylic acids. Treatment-dependent changes in gene expression were associated with treatment-dependent ESR1 binding sites, with the exception that many genes up-regulated by E2 harbored a BPA-induced ESR1 binding site but failed to show any expression change after BPA treatment. GEN and BPA exhibited a similar relationship to E2 in the breast cancer line T-47D, where cell type specificity played a much larger role than treatment specificity. Overall, both environmental estrogens clearly regulate gene expression through ESR1 on a genome-wide scale, although with lower potency resulting in less ESR1 binding sites and less gene expression changes compared to the endogenous estrogen, E2.
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