Glucocorticoid receptor-dependent gene regulatory networks.
Glucocorticoid receptor-dependent gene regulatory networks.
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糖皮质激素受体依赖性基因调节网络。
DOI：
10.1371/journal.pgen.0010016
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发表时间：
2005-08
期刊：
影响因子：
4.5
通讯作者：
Kaestner, Klaus H
中科院分区：
文献类型：
--
作者：
Phuc Le, Phillip;Friedman, Joshua R;Schug, Jonathan;Brestelli, John E;Parker, J Brandon;Bochkis, Irina M;Kaestner, Klaus H
虽然糖皮质激素调控转录的分子机制已被详细研究，但糖皮质激素受体（GR）调控的全球网络仍然未知。为了解决这个问题，我们进行了正交分析，以确定GR的直接目标。首先，我们分析了外源性糖皮质激素存在或不存在的小鼠肝脏的表达谱，导致超过1,300个差异表达的基因。然后，我们从相同的肝脏染色质上进行全基因组定位分析，确定了300多个启动子的GR。相交的两个列表产生了53个基因，其表达在功能上依赖于配体结合GR。进一步的网络和序列分析的功能目标，使我们能够建议在特定的靶基因的GR和其他转录因子之间的相互作用。总之，我们的研究结果进一步加深了我们对GR及其靶点的理解，并为更有针对性的糖皮质激素治疗提供了基础。糖皮质激素是必需的类固醇激素，合成糖皮质激素被广泛用于各种医疗条件。要了解糖皮质激素的作用机制，需要了解其表达水平受糖皮质激素信号通路调节的直接靶基因。在这篇文章中，Le及其同事利用两种高通量技术来确定体内糖皮质激素受体（GR）直接调控的基因。从注射合成糖皮质激素地塞米松的小鼠肝脏中提取RNA和染色质，并与对照组同窝小鼠进行比较。RNA表达水平的分析产生了添加地塞米松后差异表达的基因列表。对染色质的分析产生了GR与DNA结合的基因启动子序列的列表。通过交叉这两个列表，研究人员获得了由GR直接控制的基因列表，包括几个以前已知的靶点。这些直接靶点随后被用作复杂途径和序列分析的基础，这表明GR和其他转录因子之间存在多种相互作用。这项研究提供了一个医学上重要的信号通路的评估，并作为一个模型，为未来的转录调控分析。
While the molecular mechanisms of glucocorticoid regulation of transcription have been studied in detail, the global networks regulated by the glucocorticoid receptor (GR) remain unknown. To address this question, we performed an orthogonal analysis to identify direct targets of the GR. First, we analyzed the expression profile of mouse livers in the presence or absence of exogenous glucocorticoid, resulting in over 1,300 differentially expressed genes. We then executed genome-wide location analysis on chromatin from the same livers, identifying more than 300 promoters that are bound by the GR. Intersecting the two lists yielded 53 genes whose expression is functionally dependent upon the ligand-bound GR. Further network and sequence analysis of the functional targets enabled us to suggest interactions between the GR and other transcription factors at specific target genes. Together, our results further our understanding of the GR and its targets, and provide the basis for more targeted glucocorticoid therapies. Glucocorticoids are essential steroid hormones, and synthetic glucocorticoids are widely prescribed for a variety of medical conditions. Understanding the mechanism by which glucocorticoids act requires knowing the direct target genes whose expression levels are modulated by the glucocorticoid signaling pathway. In this publication, Le and colleagues have utilized two high-throughput techniques to determine genes directly regulated in vivo by the glucocorticoid receptor (GR). RNA and chromatin were extracted from the livers of mice injected with the synthetic glucocorticoid dexamethasone and compared to control littermates. The analysis of RNA expression levels generated a list of genes differentially expressed after addition of dexamethasone. The analysis of the chromatin produced a list of gene promoter sequences where the GR was bound to DNA. By intersecting the two lists, the researchers obtained a list of genes that are directly controlled by the GR, including several previously known targets. This list of direct targets was then used as the basis for complex pathways and sequence analyses, which suggested several interactions between the GR and other transcription factors. This study provides an evaluation of a medically important signaling pathway and serves as a model for future analyses of transcriptional regulation.