Glucocorticoid Receptor Activation of the Ciz1-Lcn2 Locus by Long Range Interactions
Glucocorticoid Receptor Activation of the Ciz1-Lcn2 Locus by Long Range Interactions
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DOI：
10.1074/jbc.c800212200
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发表时间：
2009-03-06
影响因子：
4.8
通讯作者：
Hager, Gordon L.
中科院分区：
文献类型：
--
作者：
Hakim, Ofir;John, Sam;Hager, Gordon L.
细胞对糖皮质激素受体（GR）激活的反应涉及一系列高度协调的调节作用，这些调节作用在多个水平上受到多种机制的影响，包括转录因子和染色质修饰剂的作用。由于大多数GR结合位点（糖皮质激素反应元件（GRES））远离启动子，因此很可能远距离相互作用在GR作用中起重要作用。为了确定长距离染色体关联是否在GR的转录调控中发挥作用，我们利用基于染色体构象捕获的技术（相关染色体陷阱）来鉴定与GR诱导的Lipocalin2（Lcn2）基因相互作用的未知的远程序列。我们的筛选显示，Lcn2 GRE与Ciz1基因相互作用，上游近30 kb。随后发现Ciz1是一个新的GR反应基因。Lcn2启动子近端的GRE显然具有调节Lcn2基因和远端Ciz1基因的功能。使用定量染色体构象捕获，我们发现，这两个基因之间的环结构。这种结构是不依赖于基因的，只存在于基因活跃的细胞类型中。不同细胞系中基因表达和环结构之间的强相关性表明，高阶相互作用在确定组织特异性基因调控中起作用。
The cellular response to glucocorticoid receptor (GR) activation involves a highly orchestrated series of regulatory actions influenced at multiple levels by a variety of mechanisms including the action of transcription factors and chromatin modifiers. Because the majority of GR binding sites (glucocorticoid-responsive elements (GREs)) are distant from promoters, it is likely that interactions at a distance play an important role in GR action. To determine whether long range chromosomal associations play a role in transcription regulation by GR, we utilized a chromosome conformation capture-based technique (associated chromosome trap) to identify unknown, remote sequences that interact with the GR-induced Lipocalin2 (Lcn2) gene. Our screen revealed that the Lcn2 GRE interacts with the Ciz1 gene, nearly 30 kb upstream. Ciz1 was subsequently found to be a novel GR-responsive gene. The GRE proximal to the Lcn2 promoter apparently functions to regulate both the Lcn2 gene and the distal Ciz1 gene. Using quantitative chromosome conformation capture, we find that a loop structure is organized between these two genes. This structure is hormone-independent and present only in cell types where the genes are active. The strong correlation between gene expression and loop structure in different cell lines suggests that high order interactions play a role in determining tissue-specific gene regulation.