Genome-Wide DNA Methylation Analysis Reveals a Potential Mechanism for the Pathogenesis and Development of Uterine Leiomyomas

Ryo Maekawa,Hiroshi Tamura,Norihiro Sugino,Maki Okada,Eiichi Takaki,Yoshiaki Yamagata,Hiromi Asada,Lifa Lee,Isao Tamura,Shun Sato,Akira Nakai,Hiromu Suzuki

doi:10.1371/journal.pone.0066632

Ryo Maekawa, Hiroshi Tamura + Show 10 more

Open Access

https://doi.org/10.1371/journal.pone.0066632

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Journal: PLoS ONE	Publication Date: Jun 20, 2013
Citations: 135	License type: CC BY 4.0

Affiliation: Yamaguchi University

Abstract

BackgroundThe pathogenesis of uterine leiomyomas, the most common benign tumor in women, remains unclear. Since acquired factors such as obesity, hypertension and early menarche place women at greater risk for uterine leiomyomas, uterine leiomyomas may be associated with epigenetic abnormalities that are caused by unfavorable environmental exposures.Principal FindingsProfiles of genome-wide DNA methylation and mRNA expression were investigated in leiomyomas and in myometrium with and without leiomyomas. Profiles of DNA methylation and mRNA expression in the myometrium with and without leiomyomas were quite similar while those in leiomyomas were distinct. We identified 120 genes whose DNA methylation and mRNA expression patterns differed between leiomyomas and the adjacent myometrium. The biological relevance of the aberrantly methylated and expressed genes was cancer process, including IRS1 that is related to transformation, and collagen-related genes such as COL4A1, COL4A2 and COL6A3. We also detected 22 target genes of estrogen receptor (ER) alpha, including apoptosis-related genes, that have aberrant DNA methylation in the promoter, suggesting that the aberrant epigenetic regulation of ER alpha-target genes contributes to the aberrant response to estrogen.ConclusionsAberrant DNA methylation and its related transcriptional aberration were associated with cancer processes, which may represent a critical initial mechanism that triggers transformation of a single tumor stem cell that will eventually develop into a monoclonal leiomyoma tumor. The aberrant epigenetic regulation of ER alpha-target genes also may contribute to the aberrant response to estrogen, which is involved in the development of uterine leiomyomas after menarche.

Highlights

Uterine leiomyomas are the most common uterine tumors in reproductive-age women with a prevalence of about 25% [1]
Aberrant DNA methylation and its related transcriptional aberration were associated with cancer processes, which may represent a critical initial mechanism that triggers transformation of a single tumor stem cell that will eventually develop into a monoclonal leiomyoma tumor
The aberrant epigenetic regulation of estrogen receptor (ER) alpha-target genes may contribute to the aberrant response to estrogen, which is involved in the development of uterine leiomyomas after menarche

Summary

Introduction

Uterine leiomyomas are the most common uterine tumors in reproductive-age women with a prevalence of about 25% [1]. Factors that lower the risk include use of hormonal contraception, smoking, giving birth and consumption of green vegetables [3,4,5]. These findings suggest that both genetic and environmental factors are involved in the development of uterine leiomyomas. The pathogenesis of uterine leiomyomas, the most common benign tumor in women, remains unclear Since acquired factors such as obesity, hypertension and early menarche place women at greater risk for uterine leiomyomas, uterine leiomyomas may be associated with epigenetic abnormalities that are caused by unfavorable environmental exposures

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