Location analysis of estrogen receptor α target promoters reveals that FOXA1 defines a domain of the estrogen response
Location analysis of estrogen receptor α target promoters reveals that FOXA1 defines a domain of the estrogen response
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DOI：
10.1073/pnas.0505575102
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发表时间：
2005-08-16
影响因子：
11.1
通讯作者：
Giguère, V
中科院分区：
文献类型：
--
作者：
Laganière, J;Deblois, G;Giguère, V
核受体可以响应其同源配体而激活靶细胞内的多种生物途径，但人们对如何在基因调控水平上实现这种区室化知之甚少。我们对 MCF-7 细胞中雌激素受体 α (ER α) 的启动子占据情况进行全基因组分析，以研究 17 β-雌二醇 (E-2) 控制乳腺癌细胞生长的分子机制。我们鉴定了 E-2 存在时与 ERa 结合的 153 个启动子。基序查找算法表明，雌激素反应元件 (ERE) 是这些启动子中最常见的基序，而传统染色质免疫沉淀测定显示这些位点上共激活子 AIB1 和 RNA 聚合酶 II 的 E-2 调节募集。这些启动子与已知的 ERa 靶标相关，但也与许多与雌激素反应不直接相关的基因相关，包括转录因子 FOXA1，其表达与乳腺肿瘤中 ER α 的存在相关。我们发现 MCF-7 细胞中 FOXA1 表达的消除抑制了 ER α 与原型 TFF1 启动子（包含 FOXA1 结合位点）的结合，阻碍了 E-2 诱导 TFF1 表达，并阻止激素诱导的细胞周期再进入。总而言之，这些结果定义了乳腺癌细胞中雌激素作用的范例，并表明核受体对基因表达的调节可以通过将其活性许可给 FOXA1 等辅助因子来划分为独特的转录域。
Nuclear receptors can activate diverse biological pathways within a target cell in response to their cognate ligands, but how this compartmentalization is achieved at the level of gene regulation is poorly understood. We used a genome-wide analysis of promoter occupancy by the estrogen receptor alpha (ER alpha) in MCF-7 cells to investigate the molecular mechanisms underlying the action of 17 beta-estradiol (E-2) in controlling the growth of breast cancer cells. We identified 153 promoters bound by ERa in the presence of E-2. Motif-finding algorithms demonstrated that the estrogen response element (ERE) is the most common motif present in these promoters whereas conventional chromatin immunoprecipitation assays showed E-2-Modulated recruitment of coactivator AIB1 and RNA polymerase II at these loci. The promoters were linked to known ERa targets but also to many genes not directly associated with the estrogenic response, including the transcriptional factor FOXA1, whose expression correlates with the presence of ER alpha in breast tumors. We found that ablation of FOXA1 expression in MCF-7 cells suppressed ER alpha binding to the prototypic TFF1 promoter (which contains a FOXA1 binding site), hindered the induction of TFF1 expression by E-2, and prevented hormone-induced reentry into the cell cycle. Taken together, these results define a paradigm for estrogen action in breast cancer cells and suggest that regulation of gene expression by nuclear receptors can be compartmentalized into unique transcriptional domains by means of licensing of their activity to cofactors such as FOXA1.