Demethylation of a nonpromoter cytosine-phosphate-guanine island in the aromatase gene may cause the aberrant up-regulation in endometriotic tissues

Izawa M, Masao Izawa, Fuminori Taniguchi, Taniguchi F, Takashi Uegaki, Uegaki T, Takai E, Eri Takai, Iwabe T, Tomio Iwabe, Naoki Terakawa, Terakawa N, Tasuku Harada, Harada T
Fertility and sterility · 2010 · vol. 95(1) , pp. 33–39 · doi:10.1016/j.fertnstert.2010.06.024 · PMID:20655525 · W2092188454
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Researchers investigated how demethylation of a nonpromoter CpG island in the aromatase gene leads to its aberrant up-regulation in endometriotic tissues.

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Abstract

ObjectiveTo search for the demethylated cytosine-phosphate-guanine (CpG) islands within the aromatase gene in stromal cells derived from endometriotic chocolate cysts.DesignProspective study.SettingDepartment of Obstetrics and Gynecology and Department of Biosignaling, Tottori University, Yonago, Japan.Patient(s)Twenty-eight women who underwent laparoscopy (n=14) and laparotomy (n=14).Intervention(s)Endometrial and endometriotic stromal cells were obtained from the uterus and chocolate cyst lining of the ovary.Main outcome measure(s)We searched for the CpG island and examined methylation profile and the association of methyl-binding proteins with the CpG island.Result(s)Up-regulation of aromatase messenger RNA (mRNA) expression was demonstrated in endometriotic cells. Three proximal promoters drove the mRNA expression. In endometrial cells, a marginal level of aromatase mRNA expression was observed. Treating endometrial cells with the demethylating agent 5-aza-2'-deoxycytidine markedly enhanced aromatase mRNA expression. The same promoters as in the endometriotic cells were used. To identify the unmethylated CpGs in endometriotic cells, we searched for CpG islands within the aromatase gene and subsequently examined the methylation profiles. Sequence analysis of bisulfite-treated genomic DNA demonstrated a stretch of CpG demethylation within a nonpromoter CpG island of the aromatase gene in endometriotic cells. In endometrial cells, the CpG sequences were heavily methylated and associated with methyl-CpG-binding proteins.Conclusion(s)The up-regulation of the aromatase gene in endometriosis may be ascribed to the epigenetic disorder associated with aberrant DNA demethylation in a nonpromoter CpG island.

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Condition tags

endometriosis

MeSH descriptors

Aromatase CpG Islands DNA Methylation Endometriosis Gene Expression Regulation, Enzymologic Aromatase Aromatase CpG Islands DNA Methylation Endometriosis Endometriosis Endometriosis Epigenesis, Genetic Epigenesis, Genetic Female Gene Expression Regulation, Enzymologic Humans Promoter Regions, Genetic RNA, Messenger RNA, Messenger

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