Reduced expression and concomitant promoter hypermethylation of HOXA10 in endometrium from women wearing intrauterine devices

Lu, Yuan; Nie, Jichan; Liu, Xishi; Guo, Sun‐Wei

doi:10.1016/j.fertnstert.2009.09.011

Cited by 8 publications

(7 citation statements)

References 33 publications

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“…In both of mouse and baboon endometriosis models, hypermethylation of the 5Ј promoter region of Hoxa10/HOXA10 and decreased Hoxa10/HOXA10 gene expression were demonstrated in eutopic endometrium (10,(41)(42). In humans, three CpG-rich fragments in the HOXA10 gene were identified (one 50 nt upstream of exon 1 and two in the intronic region flanked by exons 1 and 2), and HOXA10 was hypermethylated in all fragments in the endometrium of women with endometriosis compared with controls (43). In the present study, we observed aberrantly high PCAF expression in the eutopic endometrium of women with endometriosis compared to the normal controls.…”

Section: Discussionmentioning

confidence: 99%

PCAF Impairs Endometrial Receptivity and Embryo Implantation by Down-Regulating β3-Integrin Expression via HOXA10 Acetylation

Zhu

Sun

et al. 2013

The Journal of Clinical Endocrinology & Metabolism

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Section: Discussionmentioning

confidence: 99%

PCAF Impairs Endometrial Receptivity and Embryo Implantation by Down-Regulating β3-Integrin Expression via HOXA10 Acetylation

Zhu

Sun

et al. 2013

The Journal of Clinical Endocrinology & Metabolism

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“…This is in contrast to other studies, which have shown increased methylation of the HOXA10 gene, especially in the promoter region, in endometriosis. [50][51][52][53] The sequenom platform allows for precise measurement and quantification of DNA methylation. This may explain some of the differences seen in methylation as compared to older studies using cruder techniques.…”

Section: Discussionmentioning

confidence: 99%

Aberrant HOXA10 Methylation in Patients With Common Gynecologic Disorders: Implications for Reproductive Outcomes

2016

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HomeoboxA10 (HOXA10) is a transcription factor that is crucial for the development and patterning of the uterus during embryogenesis. In the adult endometrium, HOXA10 expression is regulated by steroid hormones and embryonic signals. Expression of sufficient HOXA10 messenger RNA is essential to endometrial receptivity and embryo implantation. Aberrant methylation is believed to alter the expression of HOXA10. Methylation of this gene may be associated with decreased fertility, implantation defects, and/or reproductive wastage seen in certain disease states that affect the female reproductive tract. This study describes the differences in methylation patterns of HOXA10 gene in uterine myomas, endometriosis, uterine septum, Asherman syndrome, or uterine polyps of women undergoing hysteroscopic surgery. In the endometrium of uteri with polyps, submucosal myomas, and intramural myomas, there were CpG sites within the HOXA10 gene that were highly methylated compared to controls. The HOXA10 gene in women with endometriosis was hypomethylated compared to controls. DNA methylation may be a common molecular mechanism that results in reproductive dysfunction seen in gynecologic disease.

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“…Promoter hypermethylation plays a major role in repressing ESR1 [38]–[40] and PGR [41]–[45] expression in human tumors. The HOXA10 promoter is also susceptible to methylation in the endometria of women wearing intrauterine devices [46], in patients with ovarian cancer [47] or endometriosis [48], and in the uteri of mice exposed to diethylstilbestrol [49]. In general, DNA methylation blocks gene expression, whereas demethylation (e.g., with 5-aza-CdR) activates gene expression.…”

Section: Discussionmentioning

confidence: 99%

5-Aza-2′-deoxycytidine Leads to Reduced Embryo Implantation and Reduced Expression of DNA Methyltransferases and Essential Endometrial Genes

et al. 2012

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BackgroundThe DNA demethylating agent 5-aza-2′-deoxycytidine (5-aza-CdR) incorporates into DNA and decreases DNA methylation, sparking interest in its use as a potential therapeutic agent. We aimed to determine the effects of maternal 5-aza-CdR treatment on embryo implantation in the mouse and to evaluate whether these effects are associated with decreased levels of DNA methyltransferases (Dnmts) and three genes (estrogen receptor α [Esr1], progesterone receptor [Pgr], and homeobox A10 [Hoxa10]) that are vital for control of endometrial changes during implantation.Methods and Principal FindingsMice treated with 5-aza-CdR had a dose-dependent decrease in number of implantation sites, with defected endometrial decidualization and stromal cell proliferation. Western blot analysis on pseudo-pregnant day 3 (PD3) showed that 0.1 mg/kg 5-aza-CdR significantly repressed Dnmt3a protein level, and 0.5 mg/kg 5-aza-CdR significantly repressed Dnmt1, Dnmt3a, and Dnmt3b protein levels in the endometrium. On PD5, mice showed significantly decreased Dnmt3a protein level with 0.1 mg/kg 5-aza-CdR, and significantly decreased Dnmt1 and Dnmt3a with 0.5 mg/kg 5-aza-CdR. Immunohistochemical staining showed that 5-aza-CdR repressed DNMT expression in a cell type–specific fashion within the uterus, including decreased expression of Dnmt1 in luminal and/or glandular epithelium and of Dnmt3a and Dnmt3b in stroma. Furthermore, the 5′ flanking regions of the Esr1, Pgr, and Hoxa10 were hypomethylated on PD5. Interestingly, the higher (0.5 mg/kg) dose of 5-aza-CdR decreased protein expression of Esr1, Pgr, and Hoxa10 in the endometrium on PD5 in both methylation-dependent and methylation-independent manners.ConclusionsThe effects of 5-aza-CdR on embryo implantation in mice were associated with altered expression of endometrial Dnmts and genes controlling endometrial changes, suggesting that altered gene methylation, and not cytotoxicity alone, contributes to implantation defects induced by 5-aza-CdR.

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Reduced expression and concomitant promoter hypermethylation of HOXA10 in endometrium from women wearing intrauterine devices

Cited by 8 publications

References 33 publications

PCAF Impairs Endometrial Receptivity and Embryo Implantation by Down-Regulating β3-Integrin Expression via HOXA10 Acetylation

PCAF Impairs Endometrial Receptivity and Embryo Implantation by Down-Regulating β3-Integrin Expression via HOXA10 Acetylation

Aberrant HOXA10 Methylation in Patients With Common Gynecologic Disorders: Implications for Reproductive Outcomes

5-Aza-2′-deoxycytidine Leads to Reduced Embryo Implantation and Reduced Expression of DNA Methyltransferases and Essential Endometrial Genes

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