Transcriptional activation of steroidogenic factor-1 by hypomethylation of the 5′ CpG island in endometriosis

Qing Xue, Zhihong Lin, Ping Yin, Magdy P. Milad, You Hong Cheng, Edmond Confino, Scott Reierstad, Serdar E. Bulun*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

147 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3261-3267
Number of pages7
JournalJournal of Clinical Endocrinology and Metabolism
Volume92
Issue number8
DOIs
StatePublished - Aug 2007

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

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