Epigenetic Regulation of E-Cadherin Controls Endometrial Receptivity

• Published in: Endocrinology (Philadelphia) Vol. 150; no. 3; pp. 1466 - 1472
• Main Authors: Rahnama, Fahimeh, Thompson, Bridget, Steiner, Michael, Shafiei, Farhad, Lobie, Peter E, Mitchell, Murray D
• Format: Journal Article
• Language: English
• Published: Chevy Chase, MD Endocrine Society 01.03.2009
• Subjects: Azacitidine - pharmacology; Biological and medical sciences; Cadherins - genetics; Cadherins - physiology; Cell Adhesion - drug effects; Cell Adhesion - genetics; Desmoplakins - genetics; Desmoplakins - metabolism; DNA (Cytosine-5-)-Methyltransferases - antagonists & inhibitors; DNA Methylation - drug effects; DNA Methylation - physiology; Embryo Implantation - genetics; Endometrium - metabolism; Endometrium - physiology; Enzyme Inhibitors - pharmacology; Epigenesis, Genetic - physiology; Female; Fundamental and applied biological sciences. Psychology; gamma Catenin; Humans; Tumor Cells, Cultured; Vertebrates: endocrinology; Uterus; E Cadherin; Endometrium; Female genital system
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2008-1142

Key to the success of human reproduction is the capacity of an embryo to attach and implant into the endometrial wall after which a nutrient supply is established through placentation. Herein, we have examined the potential epigenetic regulation of uterine receptivity by use of the receptive RL95-2 and nonreceptive AN3-CA endometrial epithelial carcinoma cell lines. Using an in vitro model of embryo implantation, we demonstrate that inhibition of DNA methylation by 5′-aza-2′-deoxycytidine (AZA), resulted in the nonreceptive AN3-CA cell line becoming receptive to BeWo cell spheroid attachment. Examination of components of the adherens junction complex revealed that AZA specifically increased the expression of E-cadherin and plakoglobin at the mRNA and protein levels in AN3-CA cells, and E-cadherin protein expression was found to localize to sites of intercellular contact. Forced expression of E-cadherin in AN3-CA cells significantly enhanced receptivity. Small interfering RNA (siRNA)-mediated depletion of the individual DNA methyltransferase (DNMT) molecules did not induce E-cadherin expression in AN3-CA cells; however, concomitant siRNA-mediated depletion of both DNMT3A and DNMT3B induced the expression of E-cadherin. Furthermore, E-cadherin expression was significantly increased after the concomitant siRNA-mediated depletion of DNMT-1, -3A, and -3B in AN3-CA cells. Therefore, we have provided evidence that E-cadherin plays an important role in uterine receptivity and that E-cadherin expression is epigenetically regulated in AN3-CA cells, suppressed by the combined actions of DNMT-1, -3A, and -3B. Inhibition of DNA methylation increases both E-cadherin expression and receptivity in an endometrial cell line, suggesting that endometrial receptivity in human pregnancy is epigenetically regulated.