Department of Genetics, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, São Paulo, Brazil.
Department of Obstetrics and Gynecology, São Paulo University (USP), São Paulo, Brazil.
Int J Mol Med. 2014 Apr;33(4):897-904. doi: 10.3892/ijmm.2014.1637. Epub 2014 Jan 28.
Endometriosis is characterized by the presence of endometrial-like tissue located outside the uterine cavity. Recent evidence suggests that endometriosis may be an epigenetic disease, as well as an estrogen-dependent disease. Based on the unique steroid hormone receptor expression profile observed in endometriotic lesions as compared to eutopic endometrium, the present study aimed to gain further insight into the DNA methylation patterns of alternative promoters of the steroid receptor genes ESR1, ESR2 and PGR in intestinal deep endometriosis, one of the most aggressive forms of endometriosis. The DNA methylation patterns were evaluated by methylation-specific polymerase chain reaction (MS-PCR) after bisulfite modification in 44 endometriotic tissues as well as in 7 matched eutopic endometrium. No differences in the DNA methylation were observed for the ESR1 and ESR2 genes. Methylation of the PGR gene was observed in 39% (17 out of 44) and 19% (7 out of 37) of the cases in the promoter regions B (PGRB) and A (PGRA), respectively. Both PGR promoter regions were methylated in 3 cases. PGRB methylated alleles were detected exclusively in the endometriotic lesions when compared to the eutopic endometrium obtained from the same patient. The effect of DNA methylation in inhibiting the PGR gene expression was corroborated by immuno-staining for PgR protein in a subset of tissue samples. The present study demonstrated that epigenetic changes occur in both promoter regions of the PGR gene in intestinal endometriosis. Since eutopic and ectopic tissues do not respond sufficiently to progesterone in women with endometriosis, further study is necessary to evaluate the effect of epigenetic alterations in progesterone-resistance in this enigmatic disease.
子宫内膜异位症的特征是子宫内膜样组织位于子宫腔外。最近的证据表明，子宫内膜异位症可能是一种表观遗传疾病，也是一种雌激素依赖性疾病。基于与在位子宫内膜相比，在子宫内膜异位症病变中观察到的独特甾体激素受体表达谱，本研究旨在进一步深入了解甾体激素受体基因 ESR1、ESR2 和 PGR 的替代启动子的 DNA 甲基化模式，这是子宫内膜异位症最具侵袭性形式之一的肠深部子宫内膜异位症。在 44 份子宫内膜异位症组织和 7 份匹配的在位子宫内膜中，通过亚硫酸氢盐修饰后的甲基化特异性聚合酶链反应 (MS-PCR) 评估 DNA 甲基化模式。ESR1 和 ESR2 基因的 DNA 甲基化无差异。PGRB 和 PGREA 启动子区域中 PGR 基因的甲基化分别在 39%（44 例中的 17 例）和 19%（37 例中的 7 例）的病例中观察到。在 3 例中同时甲基化了 PGR 两个启动子区域。与来自同一患者的在位子宫内膜相比，PGRB 甲基化等位基因仅在子宫内膜异位症病变中检测到。在一组组织样本中，对 PgR 蛋白进行免疫染色证实了 DNA 甲基化抑制 PGR 基因表达的作用。本研究表明，肠子宫内膜异位症中 PGR 基因的两个启动子区域均发生了表观遗传变化。由于患有子宫内膜异位症的女性中，在位和异位组织对孕激素的反应不足，因此需要进一步研究以评估这种神秘疾病中孕激素抵抗的表观遗传改变的影响。
