Tissue-Specific Expression of Estrogen Receptor 1 Is Regulated by DNA Methylation in a T-DMR
Tissue-Specific Expression of Estrogen Receptor 1 Is Regulated by DNA Methylation in a T-DMR
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DOI：
10.1210/me.2015-1058
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发表时间：
2016-03-01
影响因子：
--
通讯作者：
Sugino, Norihiro
中科院分区：
文献类型：
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作者：
Maekawa, Ryo;Sato, Shun;Sugino, Norihiro
雌激素受体1（ESR 1）的组织特异性表达的控制机制尚不清楚。在其他基因中，称为组织依赖性和差异甲基化区域（T-DMR）的区域的DNA甲基化与组织特异性基因表达相关。本研究调查了人类ESR 1是否具有T-DMR以及T-DMR的DNA甲基化是否调节其表达。ESR 1表达具有组织特异性，在子宫内膜和乳腺中表达较高，在胎盘和皮肤中表达较低/为零。因此，在这些组织和乳腺癌组织中分析了ESR 1启动子的DNA甲基化谱。在所有的正常组织中，近端启动子区未甲基化。另一方面，远端区域（T-DMR）在子宫内膜和乳腺中未甲基化，但在胎盘和皮肤中分别中度甲基化和高度甲基化。进行T-DMR甲基化报告基因测定以检查T-DMR处的DNA甲基化是否抑制ESR 1转录。T-DMR而不是启动子区域具有转录活性，并且T-DMR的DNA甲基化抑制ESR 1的转录。早期生长反应蛋白1可能是一个转录因子，与T-DMR结合，上调ESR 1的表达。ESR 1有多个上游外显子，每个上游外显子（Exon-A/Exon-B/Exon-C）都有自己的T-DMR。在一些乳腺癌病例和乳腺癌细胞系中，ESR 1表达不像在正常组织中那样受到T-DMR处DNA甲基化的调节。总之，ESR 1具有T-DMR。T-DMR的DNA甲基化状态与正常组织中的组织特异性ESR 1表达有关，但在乳腺癌中并不总是如此。
The mechanism controlling tissue-specific expression of estrogen receptor 1 (ESR1) is unclear. In other genes, DNA methylation of a region called the tissue-dependent and differentially methylated region (T-DMR) has been associated with tissue-specific gene expression. This study investigated whether human ESR1 has a T-DMR and whether DNA methylation of the T-DMR regulates its expression. ESR1 expression was tissue-specific, being high in the endometrium and mammary gland and low/nil in the placenta and skin. Therefore, DNA methylation profiles of the promoter of ESR1 were analyzed in these tissues and in breast cancer tissues. In all of the normal tissues, the proximal promoter regions were unmethylated. On the other hand, the distal regions (T-DMR) were unmethylated in the endometrium and mammary gland, but were moderately methylated and hypermethylated in the placenta and skin, respectively. T-DMR-methylated reporter assay was performed to examine whether DNA methylation at the T-DMR suppresses ESR1 transcription. T-DMR, but not the promoter region, had transcriptional activities and DNA methylation of the T-DMR suppressed ESR1 transcription. Early growth response protein 1 was shown to be a possible transcription factor to bind the T-DMR and up-regulate ESR1 expression. ESR1 has several upstream exons, and each upstream exon, Exon-A/Exon-B/Exon-C, had its own T-DMR. In some breast cancer cases and breast cancer cell lines, ESR1 expression was not regulated by DNA methylation at T-DMR as it is in normal tissues. In conclusion, ESR1 has a T-DMR. DNA methylation status at the T-DMR is involved in tissue-specific ESR1 expression in normal tissues but not always in breast cancer.