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Transcriptional Activation of Steroidogenic Factor-1 by Hypomethylation of the 5' CpG Island in Endometriosis

Divisions of Reproductive Biology Research (Q.X., Z.L., P.Y., Y.-H.C., S.R., S.E.B.) and Reproductive Endocrinology and Infertility (M.P.M., E.C., S.E.B.), Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611; and Department of Obstetrics and Gynecology (Q.X.), First Hospital of Peking University, Beijing, People’s Republic of China

Address all correspondence and requests for reprints to: Serdar E. Bulun, M.D., Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Northwestern University, 303 East Superior Street, Suite 4-123, Chicago, Illinois 60611. E-mail: s-bulun{at}northwestern edu.

Context: Endometriosis is an estrogen-dependent disease. Steroidogenic factor-1 (SF-1), a transcriptional factor essential for activation of multiple steroidogenic genes for estrogen biosynthesis, is undetectable in normal endometrial stromal cells and aberrantly expressed in endometriotic stromal cells.

Objective: The objective of the study was to unravel the mechanism for differential SF-1 expression in endometrial and endometriotic stromal cells.

Design: We identified a CpG island flanking the SF-1 promoter and exon I region and determined its methylation patterns in endometrial and endometriotic cells.

Setting: The study was conducted at Northwestern University.

Patients or Other Participants: Eutopic endometrium from disease-free subjects (n = 8) and the walls of cystic endometriosis lesions of the ovaries (n = 8) were investigated.

Intervention(s): Stromal cells were isolated from these two types of tissues.

Main Outcome Measure(s): Measures are mentioned in Results.

Results: SF-1 mRNA and protein levels in endometriotic stromal cells were significantly higher than those in endometrial stromal cells (P < 0.001). Bisulfite sequencing showed strikingly increased methylation in endometrial cells, compared with endometriotic cells (P < 0.001). Demethylation by 5-aza-2'-deoxycytidine increased SF-1 mRNA levels by up to 55.48-fold in endometrial cell (P < 0.05). Luciferase assays showed that the –85/+239 region bearing the CpG island regulated its activity (P < 0.01). Natural or in vitro methylation of this region strikingly reduced SF-1 promoter activity in both cell types (P < 0.01). Chromatin immunoprecipitation assay showed that methyl-CpG-binding domain protein 2 binds to the SF-1 promoter in endometrial but not endometriotic cells.

Conclusions: This is the first demonstration of methylation-dependent regulation of SF-1 in any mammalian tissue. These findings point to a new mechanism for targeting local estrogen biosynthesis in endometriosis.

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