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
The Journal of clinical endocrinology and metabolism · 2007 · vol. 92(8) , pp. 3261–3267 · doi:10.1210/jc.2007-0494 · PMID:17519303 · W1974053954
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Endometriotic stromal cells exhibit increased SF-1 expression due to hypomethylation of its 5' CpG island, unlike eutopic endometrial cells where methylation silences SF-1.

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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.

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Condition tags

endometriosis

MeSH descriptors

CpG Islands Endometriosis Homeodomain Proteins Homeodomain Proteins Receptors, Cytoplasmic and Nuclear Receptors, Cytoplasmic and Nuclear Transcriptional Activation Transcription Factors Transcription Factors Aromatase Aromatase Aromatase Inhibitors Aromatase Inhibitors Aromatase Inhibitors Azacitidine Azacitidine Azacitidine Azacitidine Blotting, Western Cells, Cultured

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