DNA hypomethylation and imbalanced expression of DNA methyltransferases (DNMT1, 3A, and 3B) in human uterine leiomyoma

Li, Shuanfang; Chiang, Tung-Chin; Richard‐Davis, Gloria; Barrett, J. Carl; McLachlan, John A.

doi:10.1016/s0090-8258(03)00194-x

Cited by 53 publications

(38 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Using the method of Restriction Landmark Genomic Scanning, we previously showed that uterine leiomyomas had aberrant DNA methylation compared with a matched patient's normal myometrium [17]. Global hypomethylation and imbalanced expression of DNA methyltransferases were also found in uterine leiomyoma [17,18]. The question "Are there diseasedependent differently methylated regions (D-DMRs) in uterine leiomyomas?"…”

mentioning

confidence: 99%

Disease-dependent Differently Methylated Regions (D-DMRs) of DNA are Enriched on the X Chromosome in Uterine Leiomyoma

Maekawa

Yagi

Ohgane

et al. 2011

Journal of Reproduction and Development

View full text Add to dashboard Cite

Abstract. Uterine leiomyoma is the most common benign tumor in women. Although responsible gene mutations have not been found in leiomyomas, they represent a progressive disease with irreversible symptoms. To characterize epigenetic features of uterine leiomyomas, the DNA methylation status of a paired sample of leiomyoma and normal myometrium was subjected to a microarray-based DNA methylation analysis with restriction tag-mediated amplification (D-REAM). In the leiomyoma, we identified an aberrant DNA methylation status for 463 hypomethylated and 318 hypermethylated genes. Although these changes occurred on all chromosomes, aberrantly hypomethylated genes were preferentially located on the X chromosome. Using paired samples of normal myometrium and leiomyoma from 6 hysterectomy patients, methylation-sensitive quantitative real-time PCR revealed 14 shared X chromosome genes with an abnormal DNA hypomethylation status (FAM9A, CPXCR1, CXORF45, TAF1, NXF5, VBP1, GABRE, DDX53, FHL1, BRCC3, DMD, GJB1, AP1S2 and PCDH11X) and one hypermethylated locus (HDAC8). Expression of XIST, which is involved in X chromosome inactivation, was equivalent in the normal myometrium and leiomyoma, indicating that the epigenetic abnormality on the X chromosome did not result from aberration of XIST gene expression. Based on these data, a unique epigenetic signature for uterine leiomyomas has emerged. The 14 hypomethylated and one hypermethylated loci provide valuable biomarkers for understanding the molecular pathogenesis of leiomyoma. Key words: Disease-dependent differently methylated regions (D-DMRs), DNA methylation, Epigenetics, Leiomyoma, X chromosome (J. Reprod. Dev. 57: 604-612, 2011) terine leiomyomas are the most common uterine tumors in reproductive-age women with a prevalence of 20-25% [1]. Leiomyomas frequently cause serious gynecological problems such as pelvic pain, menorrhagia, dysmenorrhea, infertility and recurrent pregnancy loss [2,3]. In addition, uterine leiomyomas are the most common indication for hysterectomy.Despite their high prevalence rate and distressing effect on women's reproduction, the pathogenesis of uterine leiomyomas remains unclear. Factors such as African descent, high body mass index, meat consumption, early menarche, hypertension and a history of pelvic inflammatory disease place women at greater risk for uterine leiomyoma. In contrast, women using hormonal contraception, who smoke, are parous and who consume green vegetables have lower risk [4][5][6]. These findings suggest that uterine leiomyomas develop not only by inherited genomic abnormalities but also by unfavorable environmental exposures.DNA methylation is one of the most well-characterized epigenetic marks. It is involved in gene-silencing, gene-stability and DNA duplication [7][8][9]. DNA methylation profiles define and distinguish between each type of normal cell [10,11] and have been used to characterize abnormal cells [8]. For each cell type, establishing and maintaining the specific DNA methylation profile of the cells is nece...

show abstract

mentioning

confidence: 99%

Disease-dependent Differently Methylated Regions (D-DMRs) of DNA are Enriched on the X Chromosome in Uterine Leiomyoma

Maekawa

Yagi

Ohgane

et al. 2011

Journal of Reproduction and Development

View full text Add to dashboard Cite

show abstract

“…QPCR studies performed by Sato and colleagues examining the expression of Dnmts in neonatally DES exposed C57BL/6 mice, revealed that expression of Dnmt1 and Dnmt3b was decreased at PND5 in DES-treated mice, and the pattern continued until PND14 [139]. Interestingly, it was found that human leiomyoma samples had alterations in the levels of Dnmts as well, with concomitant global hypomethylation [140].…”

Section: Des In Vivo Studiesmentioning

confidence: 99%

Effects of Endocrine-disrupting Chemicals on Female Reproductive Health

Zama¹,

Bhurke²,

Uzumcu³

2016

TOBIOTJ

View full text Add to dashboard Cite

Endocrine-disrupting chemicals (EDCs) are increasingly prevalent in the environment and the evidence demonstrates that they affect reproductive health, has been accumulating for the last few decades. In this review of recent literature, we present evidence of the effects of estrogen-mimicking EDCs on female reproductive health especially the ovaries and uteri. As representative EDCs, data from studies with a pharmaceutical estrogen, diethylstilbestrol (DES), an organochlorine pesticide methoxychlor (MXC), a phytoestrogen (genistein), and a chemical used in plastics, bisphenol a (BPA) have been presented. We also discuss the effects of a commonly found plasticizer in the environment, a phthalate (DEHP), even though it is not a typical estrogenic EDC. Collectively, these studies show that exposures during fetal and neonatal periods cause developmental reprogramming leading to adult reproductive disease. Puberty, estrous cyclicity, ovarian follicular development, and uterine functions are all affected by exposure to these EDCs. Evidence that epigenetic modifications are involved in the progression to adult disease is also presented.

show abstract

“…A global hypomethylation and differential expression of DNMT1, 3a and 3b, were revealed in uterine leiomyoma as compared with the matched normal myometria raising the possibility that epigenetic mechanisms such as DNA methylation and histone modifi cation may contribute to the development of these tumors [ 64 ].…”

Section: Epigenetics In Myomasmentioning

confidence: 99%