Role of DNA methylation in the tissue-specific expression of the CYP17A1 gene for steroidogenesis in rodents
Role of DNA methylation in the tissue-specific expression of the CYP17A1 gene for steroidogenesis in rodents
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DOI：
10.1677/joe-08-0353
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发表时间：
2009-07-01
影响因子：
4
通讯作者：
Flueck, Christa E.
中科院分区：
文献类型：
--
作者：
Missaghian, Elika;Kempna, Petra;Flueck, Christa E.
CYP17A1 基因是类固醇生成的定性调节因子。根据 CYP17 活性的存在与否，会产生盐皮质激素、糖皮质激素或肾上腺雄激素。 CYP17A1 基因的表达具有组织特异性和物种特异性。与人类不同，啮齿动物的肾上腺不表达 CYP17A1 基因，因此没有用于产生皮质醇的 P450c17 酶，但会产生皮质酮。 DNA 甲基化参与人胎盘 JEG-3 细胞中 CYP17A1 基因的组织特异性沉默。我们研究了 DNA 甲基化对于啮齿类动物 CYP17A1 基因组织特异性表达的作用。用甲基转移酶抑制剂 5-氮杂-脱氧胞苷治疗的大鼠在尿液中排出皮质醇代谢物四氢皮质醇，表明治疗通过去甲基化诱导 CYP17 表达和 17 α-羟化酶活性。因此，亚硫酸氢盐修饰实验在从大鼠肾上腺而非睾丸中提取的 DNA 中鉴定出 CYP17 启动子中的甲基化 CpG 岛。甲基转移酶和组蛋白脱乙酰酶抑制剂均诱导小鼠肾上腺皮质 Y1 细胞中 CYP17A1 基因的表达，而该细胞通常不表达 CYP17，表明小鼠 CYP17A1 基因的表达受到表观遗传控制。由小鼠 1041 bp CYP17 启动子驱动的报告构建体在 Y1 细胞中具有活性，这一发现进一步强调了 DNA 甲基化对 CYP17 表达的作用，从而排除了这些肾上腺细胞中 CYP17 表达所必需的转录因子的缺乏。内分泌学杂志 (2009) 202, 99-109
The CYP17A1 gene is the qualitative regulator of steroidogenesis. Depending on the presence or absence of CYP17 activities mineralocorticoids, glucocorticoids or adrenal androgens are produced. The expression of the CYP17A1 gene is tissue as well as species-specific. In contrast to humans, adrenals of rodents do not express the CYP17A1 gene and have therefore no P450c17 enzyme for cortisol production, but produce corticosterone. DNA methylation is involved in the tissue-specific silencing of the CYP17A1 gene in human placental JEG-3 cells. We investigated the role of DNA methylation for the tissue-specific expression of the CYP17A1 gene in rodents. Rats treated with the methyltransferase inhibitor 5-aza-deoxycytidine excreted the cortisol metabolite tetrahydrocortisol in their urine Suggesting that treatment induced CYP17 expression and 17 alpha-hydroxylase activity through demethylation. Accordingly, bisulfite modification experiments identified a methylated CpG island in the CYP17 promoter in DNA extracted from rat adrenals but not from testes. Both methyltransferase and histone deacetylase inhibitors induced the expression of the CYP17A1 gene in mouse adrenocortical Y1 cells which normally do not express CYP17, indicating that the expression of the mouse CYP17A1 gene is epigenetically controlled. The role of DNA methylation for CYP17 expression was further underlined by the finding that a reporter construct driven by the mouse - 1041 bp CYP17 promoter was active in Y1 cells, thus excluding the lack of essential transcription factors for CYP17 expression ill these adrenal cells. journal of Endocrinology (2009) 202, 99-109