Aberrant DNA methylation suppresses expression of estrogen receptor 1 (ESR1) in ovarian endometrioma

Abstract

BackgroundIn ovarian endometriomas (OE), the expression statuses of various steroid hormone receptors are altered compared with their expression statuses in eutopic endometrium (EE). For example, in OE, the expressions of estrogen receptor 1 (ESR1), which encodes ERα, and progesterone receptor (PGR) are downregulated, while the expression of ESR2, which encodes ERβ, is upregulated. The causes of these changes are unclear. DNA methylation of a specific region of a gene can result in tissue-specific gene expression. Such regions are called tissue-dependent and differentially methylated regions (T-DMRs). We previously reported that the tissue-specific expression of ESR1 is regulated by DNA methylation of a T-DMR in normal tissues. In the present study, we examined whether aberrant DNA methylation of the T-DMR is associated with the altered expressions of ESR1, ESR2 and PGR in OE.ResultsGene expression levels of ESR1, ESR2 and PGR were measured by quantitative RT-PCR. The expression levels of ESR1 and PGR were significantly lower and the expression level of ESR2 was significantly higher in OE than in EE. DNA methylation statuses were examined with an Infinium HumanMethylation450K BeadChip and sodium bisulfite sequencing. DNA methylation at the T-DMRs of ESR1 were significantly higher in OE than in EE, but no significant differences were observed in the DNA methylation statuses of ESR2 and PGR.ConclusionsAberrant DNA methylation of the T-DMR was associated with the impaired expression of ESR1, but not the altered expressions of ESR2 and PGR, in OE.

Local estrogen formation and its regulation in endometriosis

“…Although the detailed mechanisms of the attenuation of ERα and the increase in ERβ remain unclear, previous studies showed hypomethylation of the ERβ promoter could be associated with upregulation of protein level in endometriotic tissues . Maekawa et al reported the aberrant DNA methylation of tissue‐dependent and differentially methylated region (T‐DMR) in ERα contributes to its impaired expression in the ovarian endometrioma . On the other hand, in contrast to a previous report, they concluded DNA methylation is not involved in the upregulation of ERβ in endometriosis .…”

“…Maekawa et al reported the aberrant DNA methylation of tissue‐dependent and differentially methylated region (T‐DMR) in ERα contributes to its impaired expression in the ovarian endometrioma . On the other hand, in contrast to a previous report, they concluded DNA methylation is not involved in the upregulation of ERβ in endometriosis . Interestingly, other investigators showed that ERβ downregulates ERα expression in the stromal cells from ovarian endometrioma .…”

An Analysis of ESR2 and CYP19A1 Gene Expression Levels in Women With Endometriosis

“…Disorders at the level of ESR2 gene expression associated with endometriosis and related to the types and sites of lesions have been confirmed by world literature reports. The team of Maekawa et al employed RT-PCR to assay the expression levels of ESR1, ESR2 and progesterone receptor (PGR) genes in cases of ovarian endometriosis and eutopic endometrium (15). The ESR1 and PGR expression levels were substantially lower, while the level of ESR2 gene expression was significantly higher in endometriosis than in normal endometrium.…”

DNA Methylation Changes in Endometrium and Correlation with Gene Expression During Ovarian Hyper-stimulation

“…Previous studies have shown that DNA hyper-methylation has a detrimental effect on endometrial receptivity in the presence of high progesterone (P4) levels during COH [21]. E2 and P4 induced decidualization of human endometrial stromal cell in vitro has been shown to exhibit DNAm changes [18,22]. However, the status of DNAm pro les in supraphysiological E2 levels during COH and their associations with changes in gene expression remain unknown.…”