Absence of MHC class II antigen expression in trophoblast cells results from a lack of class II transactivator (CIITA) gene expression

Self Cite

268

224

Epigenetic mechanisms are involved in regulating chromatin structure and gene expression through repression. In this study, we show that histone deacetylase inhibitors (DAIs) that alter the acetylation of histones in chromatin enhance the expression of several genes on tumor cells including: MHC class I, II, and the costimulatory molecule CD40. Enhanced transcription results in a significant increase in protein expression on the tumor cell surface, and expression can be elicited on some tumors that are unresponsive to IFN-γ. The magnitude of induction of these genes cannot be explained by the effect of DAIs on the cell cycle or enhanced apoptosis. Induction of class II genes by DAIs was accompanied by activation of a repressed class II transactivator gene in a plasma cell tumor but, in several other tumor cell lines, class II was induced in the apparent absence of class II transactivator transcripts. These findings also suggest that the abnormalities observed in some tumors in the expression of genes critical to tumor immunity may result from epigenetic alterations in chromatin and gene regulation in addition to well-established mutational mechanisms.

Section: Discussionmentioning

confidence: 99%

Section: Rt and Quantitative Real-time Pcrmentioning

confidence: 99%

Activation of MHC Class I, II, and CD40 Gene Expression by Histone Deacetylase Inhibitors

Magner¹,

Kazim

Stewart

et al. 2000

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268

224

“…There is evidence that inhibition of class II gene expression on trophoblast cells is important for pregnancy outcome, as in some cases of chronic villitis of unestablished etiology (a condition associated with recurrent spontaneous abortions) class II expression is observed in the inflamed regions of the placenta (35,36). We and others have recently shown that CIITA gene expression is absent and unable to be induced by IFN-␥ treatment in trophoblast-derived cell lines (34,37). Introduction of a CIITA expression plasmid into these cell lines restores MHC class II gene expression at both the mRNA and protein levels, indicating that inhibition of CIITA expression prevents class II transcription in this cell type.…”

Section: Methylation Of Class II Trans-activatormentioning

confidence: 98%

“…Previous work demonstrated that CIITA expression in trophoblast cells is blocked at the transcriptional level (34,37). To determine the molecular mechanism responsible for this block, transcription factor assembly at the CIITA promoters was examined by IVGF.…”

Section: Factor Assembly At Ciita Promoters III and Iv Does Not Occurmentioning

confidence: 99%

Methylation of Class IItrans-Activator Promoter IV: A Novel Mechanism of MHC Class II Gene Control

Morris

Spangler

Boss

2000

Inhibition of class II trans-activator (CIITA) expression prevents embryonic trophoblast cells from up-regulating MHC class II genes in response to IFN-γ. This is thought to be one mechanism of maternal tolerance to the fetal allograft. The CIITA gene is regulated by four distinct promoters; promoter III directs constitutive (B cell) expression, and promoter IV regulates IFN-γ-inducible expression. Using in vivo genomic footprinting, promoter-reporter analysis, Southern blot analysis, and RT-PCR, we have examined the cause of CIITA silencing in a trophoblast-derived cell line. We report here that methylation of promoter IV DNA at CpG sites in Jar cells prevents promoter occupancy and IFN-γ-inducible transcription. The inhibition of CpG methylation in Jar cells by treatment with 5-aza-2′-deoxycytidine restores IFN-γ inducibility to CIITA. This is the first description of an epigenetic mechanism involved in regulation of CIITA and MHC class II gene expression.

“…The down-regulation of class II expression during differentiation of B cells to plasma cells is correlated with decreased CIITA mRNA (20). Furthermore, the inability of trophoblast cells to express class II genes, even in the presence of IFN-␥, is due to the absence of CIITA (21)(22). Transfection of CIITA expression vectors into plasma cells, trophoblasts, and IFN-␥-inducible cells such as HeLa results in constitutive class II gene expression (15-18, 20 -22).…”

mentioning

confidence: 99%

DNA Alkylating Agents Alleviate Silencing of Class II Transactivator Gene Expression in L1210 Lymphoma Cells

Murphy

Holtz

Lewandowski

et al. 2002

Self Cite

MHC class II (Ia) Ag expression is inversely correlated with tumorigenicity and directly correlated with immunogenicity in clones of the mouse L1210 lymphoma (1 ). Understanding the mechanisms by which class II Ag expression is regulated in L1210 lymphoma may facilitate the development of immunotherapeutic approaches for the treatment of some types of lymphoma and leukemia. This study demonstrates that the variation in MHC class II Ag expression among clones of L1210 lymphoma is due to differences in the expression of the class II transactivator (CIITA). Analysis of stable hybrids suggests that CIITA expression is repressed by a dominant mechanism in class II-negative L1210 clones. DNA-alkylating agents such as ethyl methanesulfonate and the chemotherapeutic drug melphalan activate CIITA and class II expression in class II negative L1210 cells, and this effect appears to be restricted to transformed cell lines derived from the early stages of B cell ontogeny. Transient transfection assays demonstrated that the CIITA type III promoter is active in class II− L1210 cells, despite the fact that the endogenous gene is not expressed, which suggests that these cells have all of the transacting factors necessary for CIITA transcription. An inverse correlation between methylation of the CIITA transcriptional regulatory region and CIITA expression was observed among L1210 clones. Furthermore, 5-azacytidine treatment activated CIITA expression in class II-negative L1210 cells. Collectively, our results suggest that 1) CIITA gene expression is repressed in class II− L1210 cells by methylation of the CIITA upstream regulatory region, and 2) treatment with DNA-alkylating agents overcomes methylation-based silencing of the CIITA gene in L1210 cells.