DNA methylation patterns of steroid receptor genes ESR1, ESR2 and PGR in deep endometriosis compromising the rectum

Abstract

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.

Identification of differentially methylated genes in the malignant transformation of ovarian endometriosis

“…RASSF2 is widely expressed in humans and its down-regulation caused by aberrant promoter methylation had been found in a variety of primary malignant tumors and tumor cell lines [21,22], but it has not been reported to be related to ovarian cancer. A study on gastric cancer suggested that RASSF2 not only suppressed tumor growth directly but also inhibited inflammation and angiogenesis by inhibiting the Ras-signaling pathway [15]. This study supported that RASSF2 was a negative effector of the Ras signaling pathway.…”

“…Study have demonstrated that epigenetic changes occur in both promoter regions B and A of the progesterone receptors (PGR) gene in intestinal EMS [15] and hypomethylation of estrogen receptor (ESR) β promoter might contribute to progesterone resistance in women with EMS [16]. ESR and PGR are quite always absent in the EAOC tissue [17], while we did not identify differentially methylated ESR and PGR genes by MCA-RDA in this study.…”

Aberrant Endometrial DNA Methylome and Associated Gene Expression in Women with Endometriosis

“…Greatest differences were observed between the proliferative (peak E 2 ) and the midsecretory (peak P 4 ) phases, suggesting that epigenetic modifications play a role in normal endometrial steroid hormone responses, which can impact the tissue's functional and physiologic roles of pregnancy establishment and maintenance, tissue homeostasis after menses and regeneration, and endometrial disorders. With regard to endometriosis, aberrant promoter methylation of several genes whose products are critical for the normal endometrial P 4 response (e.g., PGRB , HOXA10 , ESR2 , SF1 ) has been reported in eutopic endometrium and ectopic disease in the pelvis of women with endometriosis and in animal models of the disease, with resulting resistance to P 4 action [15–17]. …”

‘Omic’ high-throughput technologies in research on pathogenesis of endometriosis: a Review

“…Эпигенети-ческие изменения происходят в обоих промотерных регионах гена PGR при эндометриозе кишечника. Эутопический и эктопический эндометрий недоста-точно отвечают на действие прогестерона у женщин с эндометриозом [73].…”