Methylation of a Novel CpG Island of Intron I Is Associated With Steroidogenic Factor I Expression in Endometriotic Stromal Cells

Abstract

Steroidogenic factor 1 (SF-1), a transcriptional factor essential for estrogen biosynthesis, is undetectable in endometrial stromal cells and aberrantly expressed in endometriotic stromal cells. Objective: We tried to gain further insight into the mechanism for differential SF-1 expression in endometrial and endometriotic stromal cells. Design: We had previously identified a novel CpG island in SF-1, which is located in the downstream intron 1 region. Here, we evaluated the methylation status of this CpG island. Patients: We obtained the eutopic endometrium from disease-free participants (n ¼ 8) and the walls of cystic endometriosis lesions of the ovaries from another group of participants (n ¼ 8). None of the patients had received any preoperative hormonal therapy. Interventions: Stromal cells were isolated from these 2 types of tissues and subjected to DNA bisulfite treatment and sequence analysis. Results: The SF-1 messenger RNA (mRNA) levels in endometriotic stromal cells were significantly higher than those in endometrial stromal cells. Bisulfite sequencing showed strikingly increased methylation of a 1-kbp region around the previously identified CpG island in endometriotic cells compared with endometrial cells (P < .001). A strong correlation between SF-1 mRNA levels and percentage methylation of the intron 1 region of the SF-1 gene was observed in endometriotic cells (Spearman correlation coefficient, .96; P < .001). Conclusions: Methylation of the intron 1 region of the SF-1 gene is associated with its expression in endometriotic cells. This CpG island therefore plays an important role in regulating SF-1 expression.

An evolutionary conserved interaction between the Gcm transcription factor and the SF1 nuclear receptor in the female reproductive system

“…Our data are also in line with the recent hypothesis that transcription factors can bind demethylated as well as methylated DNA52. Finally, the high levels of expression of hNR5A1/mNR5A1 observed in endometriotic tissues are also linked to high levels of CpG methylation around exon 2 and low levels around the TSS53545556.…”

“…75), which represents the leading cause of women infertility767778. A major feature of endometriotic tissues is the overexpression of hNR5A1 and the modification of the hNR5A1 DNA methylation profile in that tissue: the hNR5A1 TSS is demethylated and the CpG island covering exon 2 is hypermethylated22535455; the present study shows that mNr5a1 expression and its DNA methylation profile are regulated by the two mGCM proteins (Fig. 6d).…”

Aberrant methylation of the IL‐12B promotor region contributes to the risk of developing ovarian endometriosis

“…To date, no reports has been found about the effect of Stage III cervical intraepithelial neoplasia on DNA methylation and mRNA expression of endometrium, so more research is needed to analyze the influence. In addition, it is worth mentioning that many endogenous and exogenous factors may have effect on global DNA methylation (Herceg, ; Scoccianti, Ricceri, & Ferrari, ; Terry, Delgado‐Cruzata, & Vin‐Raviv, ; Terry, Ferris, & Pilsner, ; Zhang, Morabia, & Carroll, ). For example, menarche age, menstrual cycle, and parity have been reported to be associated with DNA methylation in women (Demetriou, Chen, & Polidoro, ; Terry, Ferris et al, ).…”

Aberrant expression and localization of deoxyribonucleic acid methyltransferase 3B in endometriotic stromal cells

“…DNMT3B binding has been reported to affect gene expression in instances both dependent and independent of the methylation status of the DNA to which it is bound (63, 64). Consequently, we were very interested in the recruitment pattern of DNMTs in E-IUM and E-OSIS to regions of the chromatin where the methylation pattern is already established to be different between the cell types (4, 15, 45, 65). …”