Determinants of cell- and gene-specific transcriptional regulation by the glucocorticoid receptor.-猫眼课题宝

DOI：

10.1371/journal.pgen.0030094

发表时间：

2007-06

期刊：

PLoS genetics

影响因子：

4.5

通讯作者：

中科院分区：

生物学2区

文献类型：

作者：

So AY;Chaivorapol C;Bolton EC;Li H;Yamamoto KR

来源链接：

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1904358/?report=classic

糖皮质激素受体（GR）与糖皮质激素反应元件（GREs）相结合，并以细胞特异性的方式调控选择性基因转录。通常认为，天然的GREs是复合元件，可招募GR以及其他调控因子形成功能复合物。我们评估了GR的占据是否通常是GRE功能的限制决定因素，以及核心GR结合序列和GRE结构在功能位点的保守程度。我们在A549人肺细胞中，对548个已知或潜在的糖皮质激素反应基因周围100千碱基区域进行了GR占据的GREs调查。我们发现，在A549细胞中，GR主要结合于该细胞中对糖皮质激素有反应的基因附近，而非在其他细胞中受GR调控的基因处。GREs在每个反应基因上的位置是保守的，但在这组反应基因中，它们在转录起始位点的上游和下游分布均匀，其中63%距离这些位点大于10千碱基。引人注目的是，尽管这组GREs的核心GR结合序列围绕一个共有序列有很大差异，但单个GRE的精确序列在四个哺乳动物物种中是保守的。同样，核心GR结合位点两侧的序列在不同GRE之间也有差异，但在单个GRE上是保守的。我们得出结论，在A549细胞中，GR的占据是糖皮质激素反应性的主要决定因素，核心GR结合序列以及GRE结构可能蕴含基因特异性的调控信息。糖皮质激素受体（GR）通过以细胞和基因特异性的方式调节转录，调控着众多生理功能，如细胞分化和代谢。然而，决定细胞和基因特异性GR转录调控的因素尚未完全明确。我们描述了促成这种特异性的三个特性：（1）基因组中糖皮质激素反应元件（GREs）上GR的占据似乎是糖皮质激素反应性的主要决定因素；（2）GR结合的DNA序列围绕一个共有序列差异很大，但单个GRE的精确序列高度保守，这表明这些序列在基因特异性GR转录调控中发挥作用；（3）通常发现天然染色体上的GREs是复合元件，由多个因子结合位点组成，其组成变化很大，但与GR结合序列一样，在单个GRE上高度保守。此外，我们发现大多数GREs距离其GR靶基因较远，并且它们在靶基因的上游和下游分布均匀。这些发现可能适用于其他调控因子，为理解细胞和基因特异性转录调控提供了基本见解。

The glucocorticoid receptor (GR) associates with glucocorticoid response elements (GREs) and regulates selective gene transcription in a cell-specific manner. Native GREs are typically thought to be composite elements that recruit GR as well as other regulatory factors into functional complexes. We assessed whether GR occupancy is commonly a limiting determinant of GRE function as well as the extent to which core GR binding sequences and GRE architecture are conserved at functional loci. We surveyed 100-kb regions surrounding each of 548 known or potentially glucocorticoid-responsive genes in A549 human lung cells for GR-occupied GREs. We found that GR was bound in A549 cells predominately near genes responsive to glucocorticoids in those cells and not at genes regulated by GR in other cells. The GREs were positionally conserved at each responsive gene but across the set of responsive genes were distributed equally upstream and downstream of the transcription start sites, with 63% of them >10 kb from those sites. Strikingly, although the core GR binding sequences across the set of GREs varied extensively around a consensus, the precise sequence at an individual GRE was conserved across four mammalian species. Similarly, sequences flanking the core GR binding sites also varied among GREs but were conserved at individual GREs. We conclude that GR occupancy is a primary determinant of glucocorticoid responsiveness in A549 cells and that core GR binding sequences as well as GRE architecture likely harbor gene-specific regulatory information. The glucocorticoid receptor (GR) regulates a myriad of physiological functions, such as cell differentiation and metabolism, achieved through modulating transcription in a cell- and gene-specific manner. However, the determinants that specify cell- and gene-specific GR transcriptional regulation are not well established. We describe three properties that contribute to this specificity: (1) GR occupancy at genomic glucocorticoid response elements (GREs) appears to be a primary determinant of glucocorticoid responsiveness; (2) the DNA sequences bound by GR vary widely around a consensus, but the precise sequences of individual GREs are highly conserved, suggesting a role for these sequences in gene-specific GR transcriptional regulation; and (3) native chromosomal GREs were generally found to be composite elements, comprised of multiple factor binding sites that were highly variable in composition, but as with the GR binding sequences, highly conserved at individual GREs. In addition, we discovered that most GREs were positioned far from their GR target genes and that they were equally distributed upstream and downstream of the target genes. These findings, which may be applicable to other regulatory factors, provide fundamental insights for understanding cell- and gene-specific transcriptional regulation.