Demethylation of a nonpromoter cytosine-phosphate-guanine island in the aromatase gene may cause the aberrant up-regulation in endometriotic tissues.
OBJECTIVE
To search for the demethylated cytosine-phosphate-guanine (CpG) islands within the aromatase gene in stromal cells derived from endometriotic chocolate cysts.


METHODS
Prospective study.


METHODS
Department of Obstetrics and Gynecology and Department of Biosignaling, Tottori University, Yonago, Japan.


METHODS
Twenty-eight women who underwent laparoscopy (n=14) and laparotomy (n=14).


METHODS
Endometrial and endometriotic stromal cells were obtained from the uterus and chocolate cyst lining of the ovary.


METHODS
We searched for the CpG island and examined methylation profile and the association of methyl-binding proteins with the CpG island.


RESULTS
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.


CONCLUSIONS
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.
Izawa
Masao
M
Department of Biosignaling, Tottori University Faculty of Medicine, Yonago, Japan.
Taniguchi
Fuminori
F
Uegaki
Takashi
T
Takai
Eri
E
Iwabe
Tomio
T
Terakawa
Naoki
N
Harada
Tasuku
T
D001141:Aromatase / Q000235:genetics* / Q000378:metabolism; D018899:CpG Islands / Q000502:physiology*; D019175:DNA Methylation / Q000502:physiology*; D004715:Endometriosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D044127:Epigenesis, Genetic / Q000502:physiology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D017154:Stromal Cells / Q000201:enzymology / Q000473:pathology; D015854:Up-Regulation / Q000502:physiology; D014599:Uterus / Q000201:enzymology / Q000473:pathology
D012333:RNA, Messenger; D001141:Aromatase