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Mol. Hum. Reprod. Advance Access originally published online on August 13, 2008
Molecular Human Reproduction 2008 14(9):539-545; doi:10.1093/molehr/gan045
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© The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Potential link between estrogen receptor-{alpha} gene hypomethylation and uterine fibroid formation

Hiromi Asada1, Yoshiaki Yamagata1, Toshiaki Taketani1, Aki Matsuoka1, Hiroshi Tamura1, Naoko Hattori2, Jun Ohgane2, Naka Hattori3, Kunio Shiota2 and Norihiro Sugino1,4

1Department of Obstetrics and Gynecology, Yamaguchi University Graduate School of Medicine, Minamikogushi 1-1-1, Ube 755-8505, Japan 2Laboratory of Cellular Biochemistry, Animal Resource Sciences/Veterinary Medical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan 3 Institute of Life Science, Ajinomoto Co. Inc., 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki 210-8681, Japan

4 Correspondence address. Tel: +81-836-22-2286; Fax: +81-836-22-2287; E-mail: sugino{at}yamaguchi-u.ac.jp

Uterine leiomyomas are the most common uterine tumors in women. Estrogen receptor-{alpha} (ER-{alpha}) is more highly expressed in uterine leiomyomas than in normal myometrium, suggesting a link between uterine leiomyomas and ER-{alpha} expression. DNA methylation is an epigenetic mechanism of gene regulation and plays important roles in normal embryonic development and in disease progression including cancers. Here, we investigated the DNA methylation status of the ER-{alpha} promoter region (–1188 to +229 bp) in myometrium and leiomyoma. By sodium bisulfite sequencing, 49 CpG sites in the proximal promoter region of ER-{alpha} gene were shown to be unmethylated in both leiomyoma and normal myometrium. At seven CpG sites in the distal promoter region of the ER-{alpha} gene, there was a variation in DNA methylation status in myometrium and leiomyoma. Further analysis of the DNA methylation status by bisulfite restriction mapping among 11 paired samples of myometrium and leiomyoma indicated that CpG sites in the distal region of ER-{alpha} promoter are hypomethylated in leiomyomas of nine patients. In those patients, ER-{alpha} mRNA levels tended to be higher in the leiomyoma than in the myometrium. In conclusion, there was an aberrant DNA methylation status in the promoter region of ER-{alpha} gene in uterine leiomyoma, which may be associated with high ER-{alpha} mRNA expression.

Key words: DNA methylation/epigenetics/estrogen receptor-{alpha}/ER-{alpha} promoter/leiomyoma

Submitted on January 15, 2008; resubmitted on July 24, 2008; accepted on August 1, 2008.


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