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

J Clin Endocrinol Metab. 2007 Aug;92(8):3261-7. doi: 10.1210/jc.2007-0494. Epub 2007 May 22.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aromatase / biosynthesis
  • Aromatase Inhibitors / pharmacology
  • Aromatase Inhibitors / therapeutic use
  • Azacitidine / analogs & derivatives
  • Azacitidine / pharmacology
  • Azacitidine / therapeutic use
  • Blotting, Western
  • Cells, Cultured
  • Chromatin / metabolism
  • CpG Islands / genetics*
  • DNA Methylation
  • Decitabine
  • Endometriosis / genetics*
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Genes, Reporter / genetics
  • Homeodomain Proteins / biosynthesis*
  • Homeodomain Proteins / genetics*
  • Humans
  • Immunoprecipitation
  • Luciferases / genetics
  • Plasmids / genetics
  • RNA / biosynthesis
  • RNA / genetics
  • Receptors, Cytoplasmic and Nuclear / biosynthesis*
  • Receptors, Cytoplasmic and Nuclear / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Steroidogenic Factor 1
  • Transcription Factors / biosynthesis*
  • Transcription Factors / genetics*
  • Transcriptional Activation / genetics
  • Transcriptional Activation / physiology*
  • Transfection


  • Aromatase Inhibitors
  • Chromatin
  • Enzyme Inhibitors
  • Homeodomain Proteins
  • NR5A1 protein, human
  • Receptors, Cytoplasmic and Nuclear
  • Steroidogenic Factor 1
  • Transcription Factors
  • RNA
  • Decitabine
  • Luciferases
  • Aromatase
  • Azacitidine