Transcriptional activation of steroidogenic factor-1 by hypomethylation of the 5′ CpG island in endometriosis
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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The gene encoding steroidogenic factor-1 (SF-1) is hypermethylated and silenced in normal endometrial stromal cells.
“Similarly, the gene encoding for steroidogenic factor-1 (SF-1), the protein critically involved in estrogen biosynthesis, is also hypermethylated and silenced in normal endometrial stromal cells [69].”
From The Pathogenesis of Adenomyosis vis-à-vis Endometriosis (2020) · cites this paper as [69]
Higher expression of estrogen receptor amplifies estrogenic effects and the proliferative capacity of endometrial cells.
“Higher expression of estrogen receptor amplifies estrogenic effects and the proliferative capacity of endometrial cells.26,27”
From Altered genome-wide methylation in endometriosis (2014) · cites this paper as [26]
Expression of estrogen receptor b (ER-b) is significantly higher in endometriosis due to hypermethylation of the CpG islands in the estrogen receptor 2 gene.
“Expression of estrogen receptor b (ER-b) is significantly higher in endometriosis due to the hypermethylation of the CpG islands in the estrogen receptor 2 gene.25,26”
From Altered genome-wide methylation in endometriosis (2014) · cites this paper as [26]
The difference in E2 production between HESCs and ESCLs is consistent with what has been documented previously.
“The difference in E2 production between HESCs and ESCLs is consistent with what have been documented previously41–45.”
From Platelets induce increased estrogen production through NF-κB and TGF-β1 signaling pathways in endometriotic stromal cells (2020) · cites this paper as [44]
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References 47 · Cited by 219
- Authors
- Xue, Q., Lin, Z., Yin, P., Milad, M. P., Cheng, Y.-H., Confino, E., Reierstad, S., & Bulun, S. E.
- Affiliations
- Northwestern University (US)
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2007-08-01
- Volume
- 92
- Issue
- 8
- Pages
- 3261-3267
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W1974053954
- Cited by
- 219
- References
- 47
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 10 · 2023: 21 · 2022: 6 · 2021: 12 · 2020: 12 · 2019: 15 · 2018: 9 · 2017: 11 · 2016: 9 · 2015: 10 · 2014: 16 · 2013: 12 · 2012: 15
- FWCI
- 12.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01 HD38691, R01HD038691)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- endometriosis, steroidogenic factor 1, CpG island methylation, DNA methylation, promoter regulation, endometrial stromal cells, endometriotic stromal cells, estrogen synthesis, MBD2, 5-aza-2'-deoxycytidine demethylation, transcriptional activation
- MeSH terms
- Decitabine, Aromatase, Azacitidine, Cells, Cultured, Chromatin, Endometriosis, Enzyme Inhibitors, Female, Humans, Luciferases, Plasmids, RNA, Transcription Factors, Transfection, Blotting, Western, Transcriptional Activation, Genes, Reporter, Receptors, Cytoplasmic and Nuclear, Homeodomain Proteins, CpG Islands, DNA Methylation, Reverse Transcriptase Polymerase Chain Reaction, Aromatase Inhibitors, Immunoprecipitation, Steroidogenic Factor 1
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