Epigenetic regulation of E-cadherin controls endometrial receptivity.
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.
Rahnama
Fahimeh
F
Faculty of Medical and Health Sciences, National Research Centre for Growth, Development and the Liggins Institute, University of Auckland, Private Bag, Auckland, New Zealand.
Thompson
Bridget
B
Steiner
Michael
M
Shafiei
Farhad
F
Lobie
Peter E
PE
Mitchell
Murray D
MD
D001374:Azacitidine / Q000494:pharmacology; D015820:Cadherins / Q000235:genetics* / Q000502:physiology*; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors; D019175:DNA Methylation / Q000187:drug effects / Q000502:physiology; D051180:Desmoplakins / Q000235:genetics / Q000378:metabolism; D010064:Embryo Implantation / Q000235:genetics*; D004717:Endometrium / Q000378:metabolism / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000502:physiology*; D005260:Female; D006801:Humans; D014407:Tumor Cells, Cultured; D051185:gamma Catenin
D015820:Cadherins; D051180:Desmoplakins; D004791:Enzyme Inhibitors; C495292:JUP protein, human; D051185:gamma Catenin; D004248:DNA (Cytosine-5-)-Methyltransferases; D001374:Azacitidine