Genome-wide mapping of estrogen receptor-beta-binding regions reveals extensive cross-talk with transcription factor activator protein-1.
Genome-wide mapping of estrogen receptor-beta-binding regions reveals extensive cross-talk with transcription factor activator protein-1.
复制标题
DOI：
10.1158/0008-5472.can-09-4407
复制
发表时间：
2010-06
期刊：
影响因子：
11.2
通讯作者：
Chunyan Zhao;Hui Gao;Yawen Liu;Z. Papoutsi;Sadaf Jaffrey;J. Gustafsson;K. Dahlman-Wright
中科院分区：
文献类型：
--
作者：
Chunyan Zhao;Hui Gao;Yawen Liu;Z. Papoutsi;Sadaf Jaffrey;J. Gustafsson;K. Dahlman-Wright
雌激素信号传导可通过非经典途径发生，涉及雌激素受体 (ER) 与其他转录因子（如激活蛋白 1 (AP-1) 和 SP-1）的相互作用。然而，人们对这一途径的机制了解甚少，体外研究的结果相互矛盾。在这项研究中，我们应用 ChIP-on-chip 方法在全基因组范围内鉴定 ERbeta 结合位点，在 ERbeta 过表达的 MCF7 乳腺癌细胞中鉴定出 1,457 个高可信度结合位点。含有 ERbeta 结合位点的基因可以受 E2 调节。值得注意的是，大约 60% ERbeta 结合的基因组区域包含 AP-1 样结合区域和雌激素反应元件样位点，表明 AP-1 和 ERbeta 信号传导之间存在功能关联。染色质免疫沉淀 (ChIP) 分析证实了 AP-1（由致癌转录因子 c-Fos 和 c-Jun 组成）与 ERbeta 结合 DNA 区域的关联。使用 re-ChIP 检测，我们显示了 ERbeta 和 AP-1 在染色质上的共存。短干扰RNA介导的c-Fos或c-Jun表达敲除减少了ERbeta向染色质的募集，这与AP-1在介导乳腺癌细胞中雌激素信号传导中的作用一致。此外，ERα和ERβ向AP-1/ERβ靶区的募集表现出对抗雌激素反应的基因依赖性差异。总之，我们的结果通过揭示与 AP-1 转录因子的串扰，拓宽了对基因组水平 ERbeta DNA 结合的认识。
Estrogen signaling can occur through a nonclassical pathway involving the interaction of estrogen receptors (ER) with other transcription factors such as activator protein-1 (AP-1) and SP-1. However, there is little mechanistic understanding about this pathway, with conflicting results from in vitro investigations. In this study, we applied the ChIP-on-chip approach to identify ERbeta-binding sites on a genome-wide scale, identifying 1,457 high-confidence binding sites in ERbeta-overexpressing MCF7 breast cancer cells. Genes containing ERbeta-binding sites can be regulated by E2. Notably, approximately 60% of the genomic regions bound by ERbeta contained AP-1-like binding regions and estrogen response element-like sites, suggesting a functional association between AP-1 and ERbeta signaling. Chromatin immunoprecipitation (ChIP) analysis confirmed the association of AP-1, which is composed of the oncogenic transcription factors c-Fos and c-Jun, to ERbeta-bound DNA regions. Using a re-ChIP assay, we showed co-occupancy of ERbeta and AP-1 on chromatin. Short interfering RNA-mediated knockdown of c-Fos or c-Jun expression decreased ERbeta recruitment to chromatin, consistent with the role of AP-1 in mediating estrogen signaling in breast cancer cells. Additionally, ERalpha and ERbeta recruitment to AP-1/ERbeta target regions exhibited gene-dependent differences in response to antiestrogens. Together, our results broaden insights into ERbeta DNA-binding at the genomic level by revealing crosstalk with the AP-1 transcription factor.