Role of methylation in placental major histocompatibility complex antigen expression and fetal loss

The purpose of this study was to determine the role of gene methylation on major histocompatibility complex (MHC) antigen expression in the rat placenta, specifically: 1) the constitutive suppression of labyrinthine class I genes and of all class II genes, 2) genomic imprinting of class I genes, and 3) the amount of fetal loss in relationship to gene methylation. Placentas from all four mating combinations, or a subset thereof, of the inbred DA and WF strains of rats were studied simultaneously through 1) molecular assessment of their levels of methylation at various stages of pregnancy and changes in methylation after treatment with 5-azacytidine and 2) immunohistochemical determination of their MHC class I and class II antigen expression. Treatment with 5-azacytidine caused demethylation of both class I and class II genes, the level depending upon the method of administration of the drug. Treatment with 5-azacytidine did not, however, alter the expression of either the class I or class II antigens. Hence, demethylation is not involved in the constitutive suppression of labyrinthine class I genes or that of all placental class II genes, and it is not involved in the genomic imprinting of placental class I genes. The effect of 5-azacytidine on fetal loss is due to its direct cellular effects and not to an immunological mechanism.