Repression of DNA-binding dependent glucocorticoid receptor-mediated gene expression
Repression of DNA-binding dependent glucocorticoid receptor-mediated gene expression
复制标题
DOI：
10.1073/pnas.0909192106
复制
发表时间：
2009-09-29
影响因子：
11.1
通讯作者：
Dervan, Peter B.
中科院分区：
文献类型：
--
作者：
Muzikar, Katy A.;Nickols, Nicholas G.;Dervan, Peter B.
糖皮质激素受体（GR）通过DNA结合依赖性和非依赖性机制影响参与多种过程的基因的转录，包括能量代谢和免疫应答。糖皮质激素受体通过与靶基因调控区的糖皮质激素反应元件（GR）直接结合而产生DNA结合依赖性机制。不依赖于DNA结合的机制涉及GR与转录因子和共激活因子的结合，转录因子和共激活因子又与DNA接触。与GR竞争结合GRES的小分子可以通过干扰蛋白质-DNA界面来选择性地影响DNA依赖性途径。我们表明，靶向共有GRE序列的DNA结合聚酰胺与糖皮质激素诱导的拉链（GILZ）GRE结合，抑制GILZ和其他几种已知GR靶基因的表达，并降低GILZ启动子处的GR占据率。这种聚酰胺对一组糖皮质激素诱导和抑制基因的影响的全基因组表达分析可以帮助阐明这些基因的GR调节机制。
The glucocorticoid receptor (GR) affects the transcription of genes involved in diverse processes, including energy metabolism and the immune response, through DNA-binding dependent and independent mechanisms. The DNA-binding dependent mechanism occurs by direct binding of GR to glucocorticoid response elements (GREs) at regulatory regions of target genes. The DNA-binding independent mechanism involves binding of GR to transcription factors and coactivators that, in turn, contact DNA. A small molecule that competes with GR for binding to GREs could be expected to affect the DNA-dependent pathway selectively by interfering with the protein-DNA interface. We show that a DNA-binding polyamide that targets the consensus GRE sequence binds the glucocorticoid-induced zipper (GILZ) GRE, inhibits expression of GILZ and several other known GR target genes, and reduces GR occupancy at the GILZ promoter. Genome-wide expression analysis of the effects of this polyamide on a set of glucocorticoid-induced and -repressed genes could help to elucidate the mechanism of GR regulation for these genes.