CpG methylation of the PAI-1 gene 5’-flanking region is inversely correlated with PAI-1 mRNA levels in human cell lines
CpG methylation of the PAI-1 gene 5’-flanking region is inversely correlated with PAI-1 mRNA levels in human cell lines
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PAI-1 基因 5 侧翼区域的 CpG 甲基化与人类细胞系中 PAI-1 mRNA 水平呈负相关
DOI：
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发表时间：
2005
影响因子：
6.7
通讯作者：
P. Andreasen
中科院分区：
文献类型：
--
作者：
Shan Gao;S. Skeldal;A. Krogdahl;J. A. Sørensen;P. Andreasen
摘要 PAI-1的生理和病理生理功能与其在正常和患病组织中特定细胞类型的表达有关。我们分析了 DNA 甲基化对五种细胞系中 PAI-1 mRNA 水平变化的贡献。我们发现 Bowes、MCF-7 和 U937 细胞中 PAI-1 基因 -805/+152 区域的 25 个 CpG 甲基化频率不同，而在 Hep2 和 HT-1080 细胞中检测到很少或没有甲基化。 Bowes、MCF-7、U937 和 Hep2 细胞中甲基化频率与 PAI-1 mRNA 水平呈负相关，在 20 倍范围内，而 Hep2 和 HT-1080 细胞中甲基化的缺乏表明 HT-1080 细胞中甲基化水平比 Hep2 细胞高 150 倍背后的另一种机制。然而，所有细胞系在大约-1800的CpG岛中表现出10个CpG的高甲基化频率。在 Bowes、MCF-7 和 U937 中，用 5-aza-2'-deoxycytidine 处理导致 PAI-1 mRNA 水平增加约 40 倍，并且 -805/+152 区域甲基化频率大幅下降。组蛋白脱乙酰酶抑制剂曲古抑菌素 A 诱导 -805/+152 区域甲基化频率高的细胞中 PAI-1 mRNA 水平增加数倍。与匹配的正常组织相比，三个口腔鳞状细胞癌样本显示 PAI-1 5' 侧翼区域甲基化频率降低，PAI-1 mRNA 水平升高。这些结果首次表明 DNA 甲基化和组蛋白乙酰化在 PAI-1 基因的调节中，并表明如果 5' 侧翼区域没有适当的 CpG 岛，转录可能是通过 5' 侧翼区域中密度较低的 CpG 的甲基化而不是上游 CpG 岛的甲基化来调节的。
Summary The physiological and pathophysiological functions of PAI-1 are related to its expression by specific cell types in normal and diseased tissues. We analysed the contribution of DNA methylation to the variation in PAI-1 mRNA levels in five cell lines. We found varying frequencies of methylation of 25 CpGs in the -805/+152 region of the PAI-1 gene in Bowes, MCF-7 and U937 cells, while little or no methylation was detected in Hep2 and HT-1080 cells. The methylation frequency was inversely correlated with PAI-1 mRNA level within its 20-fold range in Bowes, MCF-7,U937,and Hep2 cells, while the lack of methylation in both Hep2 and HT- 1080 cells suggested another mechanism behind the 150-fold higher level in HT-1080 cells than in Hep2 cells. However, all cell lines exhibited a high frequency of methylation of 10 CpGs in a CpG island at about -1800. Treatment with 5-aza-2‘-deoxycytidine led up to circa a 40-fold increase in the PAI-1 mRNA level and a strong decrease in the frequency of methylation in the -805/+152 region in Bowes, MCF-7 and U937. The histone deacetylase inhibitor trichostatin A induced a several fold increase of the PAI-1 mRNA level in cells with a high methylation frequency of the -805/+152 region. As compared with matched normal tissue, three samples of oral squamous cell carcinomas displayed decreased frequencies of methylation of the PAI-1 5' flanking region and increased levels of PAI-1 mRNA. These results for the first time implicate DNA methylation and histone acetylation in regulation of the PAI-1 gene, and indicate that without proper CpG islands in 5’-flanking region, trancription may be regulated by methylation of less dense CpGs in the 5’-flanking region rather than methylation of upstream CpG island.
DOI：
10.1016/s0021-9258(18)54461-6
发表时间：
1991-12
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
M. Keeton;S. Curriden;A. J. Zonneveld;D. Loskutoff
通讯作者：
M. Keeton;S. Curriden;A. J. Zonneveld;D. Loskutoff
DOI：
10.1093/jnci/93.19.1465
发表时间：
2001-10-03
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
Nguyen, C;Liang, GM;Jones, PA
通讯作者：
Jones, PA