Long-Range Transcriptional Control of Progesterone Receptor Gene Expression
Long-Range Transcriptional Control of Progesterone Receptor Gene Expression
复制标题
DOI：
10.1210/me.2009-0429
复制
发表时间：
2010-02-01
影响因子：
--
通讯作者：
Nardulli, Ann M.
中科院分区：
文献类型：
--
作者：
Boney-Montoya, Jamie;Ziegler, Yvonne S.;Nardulli, Ann M.
雌激素受体α (ER α)结合特定的靶DNA序列，雌激素反应元件（EREs），调节雌激素反应基因的表达。孕激素受体（PR）基因作为雌激素反应性的标志已被广泛应用。虽然我们之前在PR-B转录起始位点的1kb内发现了与ER α相关的顺式元件，并有助于赋予雌激素反应性，但在远离转录起始位点的ER α结合位点的发现表明，该基因可能会发生远程调控。我们现在表明，PR基因的8个区域，从PR- b转录起始位点的上游311 kb到下游4 kb，与ER α相互作用，并且协同激活蛋白和乙酰化组蛋白选择性地与这些基因区域相关。特定的PR基因区域赋予雌激素对异源报告质粒的反应性，这些区域内EREs的突变减少了雌激素诱导的交互激活。重要的是，染色体构象捕获分析揭示了近端和远端PR基因区域之间的ER α(-)和配体依赖性相互作用。综上所述，我们的研究表明PR基因的远端区域参与了该基因的动态调控，近端和远端PR基因区域的协调作用使细胞能够以非凡的多功能性和敏感性响应激素水平的变化。（分子内分泌学24:346-358,2010）
Estrogen receptor alpha(ER alpha) binds to specific target DNA sequences, estrogen response elements (EREs), to regulate estrogen-responsive gene expression. The progesterone receptor (PR) gene has been used extensively as a marker of estrogen responsiveness. Although we previously identified cis elements within 1 kb of the PR-B transcription start site that are associated with ER alpha and help to confer estrogen responsiveness, the identification of ER alpha binding sites far removed from the transcription start site suggested that long-range regulation of this gene may occur. We now show that eight regions of the PR gene from 311 kb upstream to 4 kb downstream of the PR-B transcription start site interact with ER alpha and that coactivator proteins and acetylated histones are selectively associated with these gene regions. Specific PR gene regions confer estrogen responsiveness to a heterologous reporter plasmid, and mutation of EREs within these regions diminishes estrogen-induced transactivation. Importantly, chromosome conformation capture assays reveal ER alpha(-) and ligand-dependent interactions between proximal and distal PR gene regions. Taken together, our studies suggest that distal regions of the PR gene participate in the dynamic regulation of this gene and that the coordinated action of proximal and distal PR gene regions allows cells to respond to changes in hormone levels with extraordinary versatility and sensitivity. (Molecular Endocrinology 24: 346-358, 2010)