Epigenetic alterations of CYP19A1 gene in Cumulus cells and its relevance to infertility in endometriosis

Abstract

Purpose The purpose of the present study was to investigate the epigenetic mechanisms responsible for the aberrant aromatase expression (CYP19A1) in Cumulus Cells (CCs) of infertile endometriosis patients. Method Cumulus cells were obtained from 24 infertile patients with and without endometriosis who underwent ovarian stimulation for intracytoplasmic sperm injection. Expression of CYP19A1 gene was quantified using Reverse Transcription Q-PCR. DNA methylation, histone modifications, and binding of Estrogen Receptor, ERβ to regulatory DNA sequences of CYP19A1 gene were evaluated by Chromatin ImmunoPrecipitation (ChIP) assay.Results CYP19A1 gene expression in CCs of endometriosis patients was significantly lower than the control group (P = 0.04). Higher incorporation of MeCP2 (as a marker of DNA methylation) on PII and PI.4 promoters, and hypoacetylation at H3K9 in PII and hypermethylation at H3K9 in PI.4 were observed in CYP19A1 gene in endometriosis patients (P < 0.05). Moreover, a decreased level of ERβ binding to PII and an increased level of its binding to PI.3 and PI.4 promoters of CYP19A1 were observed in endometriosis patients when compared to control. Conclusion Significant reduction of CYP19A1 gene expression in CCs of endometriosis patients may be the result of epigenetic alterations in its regulatory regions, either by DNA methylation or histone modifications. These epigenetic changes along with differential binding of ERβ (as a transcription factor) in CYP19A1 promoters may impair follicular steroidogenesis, leading to poor Oocyte and embryo condition in endometriosis patients.

Aromatase/Seladin-1 Interactions in Human Neuronal Cell Culture, the Hippocampus of Healthy Rats and Transgenic Alzheimer’s Disease Mice

“…Moreover, a study performed in cell culture showed that E 2 increased seladin-1 expression by activating estrogen response element (ERE) through ERα and protected cells against Aβ toxicity; however, these effects of E 2 disappeared when seladin-1 was silenced [33]. As it was shown that the aromatase gene also has 1/2ERE sites and that estrogen is one of the major inducers of aromatase [42], the decrease in hippocampal aromatase level after chronic inhibition of seladin-1 can be related to the decreased E 2 binding to the ERE on the aromatase gene, via ERα/β activation, thereby decreasing aromatase expression. The increasing effect of estrogen on aromatase expression was found to be dependent on its binding to ERβ and the consecutive activation of ERE on the aromatase gene in human ovarian cumulus cells [42].…”

“…As it was shown that the aromatase gene also has 1/2ERE sites and that estrogen is one of the major inducers of aromatase [42], the decrease in hippocampal aromatase level after chronic inhibition of seladin-1 can be related to the decreased E 2 binding to the ERE on the aromatase gene, via ERα/β activation, thereby decreasing aromatase expression. The increasing effect of estrogen on aromatase expression was found to be dependent on its binding to ERβ and the consecutive activation of ERE on the aromatase gene in human ovarian cumulus cells [42]. Furthermore, several mechanisms underlying the effect of E 2 on aromatase expression have also been shown in other studies.…”

Association between CYP19A1, GSTM1, GSTT1, and GSTP1 genetic polymorphisms and the development of endometriosis in a Chinese population

“…Polymorphism in the CYP19A1 gene could alter an individual's susceptibility to endometriosis. Currently, many studies have indicated that CYP19A1 polymorphisms are associated with endometriosis development, and have revealed that these genetic polymorphisms are correlated with high levels of estrogen (Haiman et al, 2007;Allen et al, 2008;Hosseini et al, 2016). rs2899470 is located in the intron portion of the CYP19A1 gene, and is associated with levels of steroid hormones, such as testosterone and estrogen (Bulun et al, 2003;Barrett et al, 2005).…”

“…E 2 /T ratio is an important indicator of aromatase activity, which is responsible for aromatization of androgens into estrogens (Jin et al, 2009). CYP19A1 gene polymorphism is associated with reduced aromatase activity, which can lead to the development of endometriosis (Wang et al, 2010;Zaree et al, 2015;Hosseini et al, 2016;Abu Hashim, 2016). While previous studies have investigated the association between CYP19A1 and risk of endometriosis, the results were inconsistent (Hur et al, 2007;Vietri et al, 2009;Yang et al, 2010;Szczepańska et al, 2013;Wang et al, 2012Wang et al, , 2014.…”

Aromatase P450 activity in the natural menstrual cycle and during controlled ovarian stimulation

“…Однако De Abreu et al сообщили, что НГЭ не оказывает существенного влияния на экспрессию гена CYP19A1 в клетках грану-лезы пациенток в протоколах ЭКО [64]. По дан-ным E. Hosseini et al [65], в клетках кумулю-са пациенток с НГЭ экспрессия гена CYP19A1 значительно ниже по сравнению с пациент-ками без НГЭ. Эти данные соответствуют ре-зультатам Barcelos et al о низком уровне мРНК ароматазы в кумулюсных клетках пациенток с НГЭ [66].…”