Michigan State University, College of Human Medicine, Grand Rapids, MI, USA.
Eidgenossische Technische Hochschule Zurich, Zurich, Switzerland.
Mol Hum Reprod. 2021 May 29;27(6). doi: 10.1093/molehr/gaab018.
About 40% of women with infertility and 70% of women with pelvic pain suffer from endometriosis. The pregnancy rate in women undergoing IVF with low endometrial integrin αvβ3 (LEI) expression is significantly lower compared to the women with high endometrial integrin αvβ3 (HEI). Mid-secretory eutopic endometrial biopsies were obtained from healthy controls (C; n=3), and women with HEI (n=4) and LEI (n=4) and endometriosis. Changes in gene expression were assessed using human gene arrays and DNA methylation data were derived using 385 K Two-Array Promoter Arrays. Transcriptional analysis revealed that LEI and C groups clustered separately with 396 differentially expressed genes (DEGs) (P<0.01: 275 up and 121 down) demonstrating that transcriptional and epigenetic changes are distinct in the LEI eutopic endometrium compared to the C and HEI group. In contrast, HEI vs C and HEI vs LEI comparisons only identified 83 and 45 DEGs, respectively. The methylation promoter array identified 1304 differentially methylated regions in the LEI vs C comparison. The overlap of gene and methylation array data identified 14 epigenetically dysregulated genes and quantitative RT-PCR analysis validated the transcriptomic findings. The analysis also revealed that aryl hydrocarbon receptor (AHR) was hypomethylated and significantly overexpressed in LEI samples compared to C. Further analysis validated that AHR transcript and protein expression are significantly (P<0.05) increased in LEI women compared to C. The increase in AHR, together with the altered methylation status of the 14 additional genes, may provide a diagnostic tool to identify the subset of women who have endometriosis-associated infertility.
约 40%的不孕女性和 70%的盆腔疼痛女性患有子宫内膜异位症。与子宫内膜整合素αvβ3（LEI）高表达的女性相比，接受 IVF 治疗且 LEI 表达水平低的女性的妊娠率显著降低。从中期分泌期采集健康对照组（C；n=3）、HEI（n=4）和 LEI（n=4）以及子宫内膜异位症患者的在位子宫内膜活检。使用人类基因芯片评估基因表达变化，并使用 385K 双芯片启动子芯片获得 DNA 甲基化数据。转录分析显示，LEI 和 C 组分别聚类，有 396 个差异表达基因（DEGs）（P<0.01：275 个上调和 121 个下调），表明与 C 和 HEI 组相比，LEI 在位子宫内膜的转录和表观遗传变化明显不同。相比之下，HEI 与 C 和 HEI 与 LEI 的比较分别仅鉴定出 83 个和 45 个 DEGs。甲基化启动子芯片在 LEI 与 C 的比较中鉴定出 1304 个差异甲基化区域。基因和甲基化芯片数据的重叠确定了 14 个表观遗传失调基因，定量 RT-PCR 分析验证了转录组学发现。该分析还表明，与 C 相比，芳香烃受体（AHR）在 LEI 样本中低甲基化且显著过表达。进一步分析验证了 AHR 转录物和蛋白质表达在 LEI 女性中显著增加（P<0.05）。AHR 的增加，以及另外 14 个基因的甲基化状态改变，可能为识别具有子宫内膜异位症相关不孕的女性亚群提供一种诊断工具。
