Epigenetic regulation of 11β-hydroxysteroid dehydrogenase type 2 expression
Epigenetic regulation of 11β-hydroxysteroid dehydrogenase type 2 expression
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DOI：
10.1172/jci200421647
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发表时间：
2004-10-01
影响因子：
15.9
通讯作者：
Frey, BM
中科院分区：
文献类型：
--
作者：
Alikhani-Koopaei, R;Fouladkou, F;Frey, BM
11β -羟基类固醇脱氢酶2型（11betaHSD2）在醛固酮靶组织中选择性表达，通过灭活11β -羟基糖皮质激素，使醛固酮对矿糖皮质激素受体具有选择性。11betaHSD2的可变活性与血压控制和高血压有关。本研究旨在阐明一种表观遗传机制，即DNA甲基化，是否解释了编码11betaHSD2， HSD11D2的基因表达的严格控制。覆盖HSD11B2启动子和外显子1的CpG岛在HSD11B2低表达的组织和细胞系中被发现密集甲基化，而在HSD11B2高表达的组织和细胞系中没有。5-aza-2'-脱氧胞苷和普鲁卡因酰胺诱导的去甲基化增强了人细胞和大鼠体内11betaHSD2酶的转录和活性。HSD11B2启动子-荧光素酶结构的甲基化降低了转录活性。转录因子识别序列的甲基化，包括Sp1/Sp3、Arnt和核因子1 （NF1）的识别序列，降低了它们的dna结合活性。本文确定NF1为强HSD11B2刺激因子。NF1的作用依赖于CpGs的位置和CpGs的甲基化组合。甲基化的cpg结合蛋白复合物1转录抑制直接与甲基化的HSD11B2启动子相互作用。这些结果表明DNA甲基化在HSD11B2基因抑制中的作用，并提示影响该基因与高血压因果关系的表观遗传机制。
The enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) is selectively expressed in aldosterone target tissues, where it confers aldosterone selectivity for the mineralocorticoid receptor by inactivating 11beta-hydroxy-glucocorticoids. Variable activity of 11betaHSD2 is relevant for blood pressure control and hypertension. The present investigation aimed to elucidate whether an epigenetic mechanism, DNA methylation, accounts for the rigorous control of expression of the gene encoding 11betaHSD2, HSD11D2. CpG islands covering the promoter and exon 1 of HSD11B2 were found to be densely methylated in tissues and cell lines with low expression but not those with high expression of HSD11B2. Demethylation induced by 5-aza-2'-deoxycytidine and procainamide enhanced the transcription and activity of the 11betaHSD2 enzyme in human cells in vitro and in rats in vivo. Methylation of HSD11B2 promoter-luciferase constructs decreased transcriptional activity. Methylation of recognition sequences of transcription factors, including those for Sp1/Sp3, Arnt, and nuclear factor 1 (NF1) diminished their DNA-binding activity. Herein NF1 was identified as a strong HSD11B2 stimulatory factor. The effect of NF1 was dependent on the position of CpGs and the combination of CpGs methylated. A methylated-CpG-binding protein complex 1 transcriptional repression interacted directly with the methylated HSD11B2 promoter. These results indicate a role for DNA methylation in HSD11B2 gene repression and suggest an epigenetic mechanism affecting this gene causally linked with hypertension.