Hypermethylation of the CpG Island Spanning From Exon II to Intron III is Associated With Steroidogenic Factor 1 Expression in Stromal Cells of Endometriosis

Qing Xue, Xue Q, Ying Fang Zhou, Ying Zhou, Zhou YF, Zhu SN, Sai Nan Zhu, Serdar E. Bulun, Bulun Se
Reproductive sciences (Thousand Oaks, Calif.) · 2011 · vol. 18(11) , pp. 1080–1084 · doi:10.1177/1933719111404614 · PMID:21926385 · PMC3343144 · W1982107116
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Hypermethylation of a specific CpG island in the SF-1 gene correlates with increased SF-1 expression in endometriosis stromal cells compared to normal endometrium.

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This study examined why steroidogenic factor 1 (SF-1) is differentially expressed between endometrial and endometriosis-derived stromal cells by analyzing a novel CpG island in the SF-1 gene spanning from exon II to intron III. Stromal cells were isolated from eutopic endometrium of disease-free participants (n = 8) and ovarian cystic endometriosis lesion walls (n = 8) without preoperative hormonal therapy, and SF-1 mRNA levels were compared with CpG methylation using bisulfite sequencing. SF-1 mRNA was significantly higher in endometriotic stromal cells and showed a strong positive correlation with the percentage methylation of the exon II/intron III region (Pearson r = 0.98, P < .001), with markedly increased methylation in endometriotic cells; the paper does not test causal mechanisms beyond the correlation. This paper is centrally about endometriosis — it links exon II/intron III CpG island hypermethylation in the SF-1 gene to SF-1 expression in endometriosis-derived stromal cells.

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Abstract

UnlabelledEndometriosis is an estrogen-dependent disease. Steroidogenic factor 1 (SF-1), a transcription factor, is essential for the activation of multiple steroidogenic genes for estrogen biosynthesis in endometriosis-derived stromal cells.ObjectiveUnravel the mechanism for differential SF-1 expression in endometrial and endometriotic stromal cells.DesignWe identified a novel CpG island in the SF-1 gene, which spans from exon II to intron III. We evaluated the methylation status of this CpG island.PatientsEutopic endometrium from disease-free participants (n = 8) and the walls of cystic endometriosis lesions of the ovaries (n = 8). None of the patients had received any preoperative hormonal therapy. Stromal cells were isolated from these 2 types of tissues.ResultsSF-1 messenger RNA (mRNA) levels in endometriotic stromal cells were significantly higher than those in endometrial stromal cells. Bisulfite sequencing showed strikingly increased methylation in endometriotic cells compared with endometrial cells (P < .001). A strong correlation between mRNA levels and percentage methylation of the exon II/intron III are observed. Specifically, the Pearson correlation coefficient was .98 (P < .001) for this association.ConclusionsWe demonstrated that methylation of a coding exon/intron sequence in the SF-1 gene positively regulated its expression in endometriosis, whereas its hypomethylation in normal endometrium was associated with drastically lower SF-1 levels.
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Abstract

Endometriosis is an estrogen-dependent disease. Steroidogenic factor 1 (SF-1), a transcription factor, is essential for the activation of multiple steroidogenic genes for estrogen biosynthesis in endometriosis-derived stromal cells.

Objective

Unravel the mechanism for differential SF-1 expression in endometrial and endometriotic stromal cells. DESIGN: We identified a novel CpG island in the SF-1 gene, which spans from exon II to intron III. We evaluated the methylation status of this CpG island. PATIENTS: Eutopic endometrium from disease-free participants (n = 8) and the walls of cystic endometriosis lesions of the ovaries (n = 8). None of the patients had received any preoperative hormonal therapy. Stromal cells were isolated from these 2 types of tissues.

Results

SF-1 messenger RNA (mRNA) levels in endometriotic stromal cells were significantly higher than those in endometrial stromal cells. Bisulfite sequencing showed strikingly increased methylation in endometriotic cells compared with endometrial cells (P < .001). A strong correlation between mRNA levels and percentage methylation of the exon II/intron III are observed. Specifically, the Pearson correlation coefficient was .98 (P < .001) for this association.

Conclusions

We demonstrated that methylation of a coding exon/intron sequence in the SF-1 gene positively regulated its expression in endometriosis, whereas its hypomethylation in normal endometrium was associated with drastically lower SF-1 levels. Similar content being viewed by others

References

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Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article Xue, Q., Zhou, Y.F., Zhu, S.N. et al. Hypermethylation of the CpG Island Spanning From Exon II to Intron III is Associated With Steroidogenic Factor 1 Expression in Stromal Cells of Endometriosis. Reprod. Sci. 18, 1080–1084 (2011). https://doi.org/10.1177/1933719111404614 Published: Issue date: DOI: https://doi.org/10.1177/1933719111404614

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endometriosis

MeSH descriptors

CpG Islands DNA Methylation Endometriosis Steroidogenic Factor 1 Stromal Cells Adult Cells, Cultured CpG Islands DNA Methylation Endometriosis Exons Exons Female Gene Expression Humans Introns Introns Real-Time Polymerase Chain Reaction RNA, Messenger RNA, Messenger

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