Repression of MHC class II gene transcription in trophoblast cells by novel single-stranded DNA binding proteins

Murphy, Shawn P.; Gollnick, Sandra O.; Pazmany, Tamas; Maier, Patricia; El'kin, G. É.; Tomasi, Thomas B.

doi:10.1002/(sici)1098-2795(199708)47:4<390::aid-mrd5>3.0.co;2-f

Cited by 13 publications

(5 citation statements)

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“…A negative regulatory element has been located in a murine H-2 class I negative embryonal carcinoma cell line that is 180 bp upstream from the transcription start site. In agreement with the idea of unique negative regulation of MHC antigens in this cell type, Murphy et al (1997) have recently reported that trophoblast cells in several species restrict class II expression by this mechanism. The study included cell lines we had generated from the placentas of gestation day 9/10 Swiss-Webster mice which served as controls in the present experiments.…”

Section: Discussionsupporting

confidence: 70%

Differential expression and regulation of a human transgene, HLA-B27, in mouse placental and embryonic cell lines

Hunt

Banerjee²,

Pace³

1998

Molecular Human Reproduction

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Unlike other somatic cells, human placental trophoblast cells do not express the highly polymorphic HLA-A and HLA-B human leukocyte major histocompatibility antigens that would stimulate maternal immunological rejection of the fetus. To investigate mechanisms underlying cell lineage-specific expression, cell lines were generated from homozygous matings of HLA-B27 transgenic mice. Trophoblast cell lines were generated from gestation day 10 placentas and fibroblasts were cultured from gestation day 13/14 embryos. Polymerase chain reaction (PCR) readily identified HLA-B DNA in transgenic trophoblastic cells but specific mRNA was of low abundance, being detectable by reverse transcriptase PCR but not by Northern blot hybridization. HLA-B-specific protein in/on the trophoblast cells was undetectable by cell enzyme-linked immunosorbent assay and the protein was not induced by exposing the trophoblastic cells to interferon-gamma (IFN-gamma). Restricted expression was specific for the HLA-B transgene and its antigen; IFN-gamma-inducible endogenous H-2Db class I antigens were detectable on the trophoblast cells. In contrast to the trophoblastic cells, HLA-B27 transgenic fibroblasts expressed IFN-gamma-inducible HLA class I antigens as well as H-2Db antigens. Thus, the mechanism(s) regulating expression of the polymorphic HLA-B antigen in trophoblastic cells is gene-specific, IFN-gamma-resistant and operative at the level of transcription or immediate post-transcription.

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Section: Discussionsupporting

confidence: 70%

Differential expression and regulation of a human transgene, HLA-B27, in mouse placental and embryonic cell lines

Hunt

Banerjee²,

Pace³

1998

Molecular Human Reproduction

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“…Indeed, it has been shown that mouse embryos express polymorphic MHC molecules in the second half of gestation only and at a much reduced level compared with adult tissues (David-Watines, 1990;Morello et al, 1985;Ozato et al, 1985). Moreover, and despite much earlier controversy, the weight of evidence indicates that trophectoderm-derived tissues of the placenta, at the maternal-fetal interface, are deprived of such antigens throughout gestation (Hunt et al, 1987(Hunt et al, , 1988Kawata et al, 1984;Murphy et al, 1997). Thus we started to test this hypothesis by producing transgenic mice expressing polymorphic MHC class I molecules (H-2K b ) early in embryogenesis, including at the maternal-fetal interface, and analyzing the consequences for fetal development.…”

Section: Discussionmentioning

confidence: 99%

Selective loss of mouse embryos due to the expression of transgenic major histocompatibility class I molecules early in embryogenesis

Aït-Azzouzene¹,

Langkopf²,

Cohen³

et al. 1998

Mol. Reprod. Dev.

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Among the numerous hypotheses proposed to explain the absence of fetal rejection by the mother in mammals, it has been suggested that regulation of expression of the polymorphic major histocompatibility complex (MHC) at the fetal‐maternal interface plays a major role. In addition to a lack of MHC gene expression in the placenta throughout gestation, the absence of polymorphic MHC molecules on the early embryo, as well as their low level of expression after midgestation, could contribute to this important biologic phenomenon. In order to test this hypothesis, we have produced transgenic mice able to express polymorphic MHC class I molecules early in embryogenesis. We have placed the MHC class Ia gene H‐2Kb under the control of a housekeeping gene promoter, the hydroxy‐methyl‐glutaryl coenzyme A reductase (HMG) gene minimal promoter. This construct has been tested for functionality after transfection into mouse fibroblast L cells. The analysis of three founder transgenic mice and their progeny suggested that fetoplacental units that could express the H‐2Kb heavy chains are unable to survive in utero beyond midgestation. We have shown further that a much higher resorption rate, on days 11 to 13 of embryonic development, is observed among transgenic embryos developing from eggs microinjected at the one‐cell stage with the pHMG‐Kb construct than in control embryos. This lethality is not due to immune phenomena, since it is observed in histocompatible combinations between mother and fetus. These results are discussed in the context of what is currently known about the regulation of MHC expression at the fetal‐maternal interface and in various transgenic mouse models. Mol. Reprod. Dev. 50:35–44, 1998. © 1998 Wiley‐Liss, Inc.

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“…The 300-18 cells (29) were a generous gift from Dr. R. Lynch (University of Iowa, Iowa City, Iowa). All other cell lines were grown as previously described (21,30).…”

Section: Cell Culturementioning

confidence: 99%

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

Murphy

Holtz

Lewandowski

et al. 2002

The Journal of Immunology

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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.

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Repression of MHC class II gene transcription in trophoblast cells by novel single-stranded DNA binding proteins

Cited by 13 publications

References 58 publications

Differential expression and regulation of a human transgene, HLA-B27, in mouse placental and embryonic cell lines

Differential expression and regulation of a human transgene, HLA-B27, in mouse placental and embryonic cell lines

Selective loss of mouse embryos due to the expression of transgenic major histocompatibility class I molecules early in embryogenesis

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

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