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Class II Transactivator (CIITA) Promoter Methylation Does Not Correlate with Silencing of CIITA Transcription in Trophoblasts¹

Department of Immunology,³ Roswell Park Cancer Institute, Buffalo, New York 14263 Department of Anatomy and Cell Biology,⁴ University of Kansas Medical Center, Kansas City, Kansas 66160 Department of Basic Sciences,⁵ Mercer University School of Medicine, Macon, Georgia 31207

Trophoblast cells are unique because they do not express major histocompatibility complex (MHC) class II antigens, either constitutively or after exposure to interferon- (IFN-). The absence of MHC class II antigens on trophoblasts is thought to play a critical role in preventing rejection of the fetus by the maternal immune system. The inability of trophoblasts to express MHC class II genes is primarily due to lack of the class II transactivator (CIITA), a transacting factor that is required for constitutive and IFN--inducible MHC class II transcription. We, therefore, investigated the silencing of CIITA expression in trophoblasts. In transient transfection assays, transcription from the IFN--responsive CIITA type IV promoter was upregulated by IFN- in trophoblasts, which suggests that CIITA is silenced by an epigenetic mechanism in these cells. Polymerase chain reaction analysis demonstrated that the CIITA type IV promoter is methylated in both the human choriocarcinoma cell lines JEG-3 and Jar and in 2fTGH fibrosarcoma cells, which are IFN- inducible for CIITA. Conversely, methylation of the CIITA type IV promoter was not observed in human primary cytotrophoblasts isolated from term placentae or in mouse or rat trophoblast cell lines. Simultaneous treatment with IFN- and the histone deacetylase inhibitor trichostatin A weakly activated CIITA transcription in mouse trophoblasts. Stable hybrids between human choriocarcinoma and fibrosarcoma cells and between mouse trophoblasts and fibroblasts expressed CIITA following treatment with IFN-. These results suggest that silencing of CIITA transcription is recessive in trophoblasts and involves an epigenetic mechanism other than promoter methylation. The fact that CIITA is expressed in the stable hybrids implies that trophoblasts may be missing a factor that regulates chromatin structure at the CIITA promoter.

¹ This work was supported by grants from the National Institutes of Health (R01 HD37464 to S.P.M. and R01 HD24217 to J.S.H.), the Buffalo Foundation, the Roswell Park Alliance, and the Roswell Park Cancer Center Support Grant P30 CA 16056 to S.P.M., and a Lied Basic Science Pilot Research Grant to M.G.P. J.C. was supported by National Cancer Institute predoctoral training grant 55640201.

² Correspondence: Shawn P. Murphy, Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. FAX: 716 845 8906; shawn.murphy{at}roswellpark.org

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