Experimental Murine Endometriosis Induces DNA Methylation and Altered Gene Expression in Eutopic Endometrium1

Abstract

The eutopic endometrium in women with endometriosis demonstrates diminished endometrial receptivity and altered gene expression. It is unknown if the endometrium being defective gives rise to a predisposition toward endometriosis and infertility or, alternatively, if endometriosis causes the altered endometrial receptivity. Here we created experimental endometriosis in mice and examined the expression of several markers of endometrial receptivity in the eutopic endometrium. Methylation of Hoxa10 was also evaluated as a potential mechanism responsible for altered gene expression. Expression of each gene was measured using quantitative real-time RT-PCR at 14 wk after induction of endometriosis. Expression of Hoxa10 and Hoxa11, which are necessary for endometrial receptivity, were decreased in the endometriosis group. Insulin-like growth factor binding protein-1 (Igfbp1) mRNA was decreased in the endometriosis group. However, there was no change in Integrin beta3 (Itgb3) mRNA expression. Total progesterone receptor (Pgr-AB) was increased in the endometriosis group and the ratio of Pgr-B to Pgr-AB was increased, indicating a shift from Pgr-A to Pgr-B expression. Basic transcription element-binding protein-1 (Bteb1), official symbol and name Klf9, Kruppel-like factor 9, which functionally interacts with Pgr in endometrium, was also decreased in the endometriosis group. In addition, hypermethylation of Hoxa10 in the endometriosis group was shown by methylation-specific PCR and confirmed by bisulfite sequencing. These findings demonstrate that normal endometrium, when placed in an ectopic location to create experimental endometriosis, led to characteristic changes in gene expression in eutopic endometrium. These data suggest the existence of a signal conduction pathway from endometriosis that alters endometrial gene expression through altered Pgr signaling and epigenetic programming.

The Role ofHoxGenes in Female Reproductive Tract Development, Adult Function, and Fertility

“…In humans, the expression of both HOXA10 and HOXA11 rises dramatically during the implantation window and remains elevated throughout the secretory phase. However, patients with endometriosis do not show this rise in HOXA10 and HOXA11 (Taylor et al 1999a;Kim et al 2007;Lee et al 2009). …”

“…These epigenetic changes have been described in numerous studies including hypermethylation of HOXA10, progesterone receptor-b, and E-cadherin or hypomethylation of genes for estrogen receptor-b and steroidogenic factor 1 (Guo 2009;Senapati and Barnhart 2011). In both murine and baboon endometriosis models, hypermethylation of the promoter region of Hoxa10/HOXA10 and decreased expression of Hoxa10/HOXA10 genes were shown in eutopic endometrium (Kim et al 2007;Lee et al 2009). In humans, hypermethylation of HOXA10 was identified in the endometrium of women with endometriosis (Wu et al 2005).…”

‘Omic’ high-throughput technologies in research on pathogenesis of endometriosis: a Review

“…Ген HOXA10, как известно, играет важную роль в развитии эндометри-оза и связанном с ним бесплодии, влияя на форми-рование смещения эндометриальных клеток в тече-ние эмбрионального развития и влияя на рецептив-ность эндометрия. По сравнению с эутопическим эндометрием в эктопическом эндометрии было най-дено систематическое снижение экспрессии HOXA10 кластерных генов [77,78]. S. Jana и соавт.…”

“…S. Jana и соавт. [40,78] также нашли значительно более низкую экс-прессию HOXA-10 и HOXA-11 у женщин с эндоме-триозом по сравнению с женщинами без этого забо-левания. Предполагается, что отклонение в экспрес-сии HOXA-10 и HOXA-11 генов оказывает негатив-ное влияние на эндометриальную реконструкцию и экспрессию маркеров восприимчивости [40,78].…”

“…[40,78] также нашли значительно более низкую экс-прессию HOXA-10 и HOXA-11 у женщин с эндоме-триозом по сравнению с женщинами без этого забо-левания. Предполагается, что отклонение в экспрес-сии HOXA-10 и HOXA-11 генов оказывает негатив-ное влияние на эндометриальную реконструкцию и экспрессию маркеров восприимчивости [40,78]. В других исследованиях [79] более низкую экспрессию гена HOXA10 в эутопической и эктопической эндо-метриальной ткани от женщин с эндометриозом свя-зывают не только с патогенезом эндометриоза, но и с эндометриозассоциированным бесплодием.…”