Abstract
IFN-gamma is a potent pleiotropic Th1 cytokine, the production of which is tightly regulated during fetal development. Negative control of fetal/neonatal IFN-gamma production is generally attributed to the Th1-antagonistic effect of mediators produced by the placenta, but evidence exists of additional and more direct transcriptional regulation. We report that neonatal (cord blood) CD3(+)/CD45RO(-) T cells, in particular the CD4(+)/CD45RO(-) subset, are hypermethylated at CpG and non-CpG (CpA and CpT) sites within and adjacent to the IFN-gamma promoter. In contrast, CpG methylation patterns in cord blood IFN-gamma-producing CD8(+)/CD45RO(-) T cells and CD56(+)/CD16(+)/CD3(-) NK cells did not differ significantly from those in their adult counterparts. Consistent with this finding, IFN-gamma production by stimulated naive cord blood CD4(+) T cells is reduced 5- to 10-fold relative to adult CD4(+) T cells, whereas production levels in neonatal and adult CD8(+) T cells are of a similar order. Evidence of significant CpA and CpT methylation was not discovered in promoter sequence from other cytokines (IL-4, TNF-alpha, or IFN-gammaR alpha-chain). We additionally demonstrate that overexpression of DNA methyltransferase 3a in embryonic kidney carcinoma cells is accompanied by CpA methylation of the IFN-gamma promoter.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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5-Methylcytosine
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Adenine / metabolism
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Adult
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CD3 Complex / biosynthesis
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Calcium-Binding Proteins
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Cloning, Molecular
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CpG Islands / drug effects
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CpG Islands / immunology*
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Cytosine / analogs & derivatives*
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Cytosine / metabolism
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DNA Methylation*
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DNA Methyltransferase 3A
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Dinucleotide Repeats / immunology
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Fetal Blood / immunology
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Fetal Blood / metabolism*
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Gene Expression Regulation / immunology*
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Humans
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Infant, Newborn
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Interferon-gamma / genetics*
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Interferon-gamma / metabolism*
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Interleukin-4 / genetics
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Interleukin-4 / metabolism
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Leukocyte Common Antigens / biosynthesis*
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Microfilament Proteins
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Promoter Regions, Genetic / drug effects
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Promoter Regions, Genetic / immunology*
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Sequence Analysis, DNA
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Sulfites / pharmacology
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism*
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Thymine / metabolism
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
Substances
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AIF1 protein, human
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CD3 Complex
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Calcium-Binding Proteins
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DNA-Binding Proteins
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DNMT3A protein, human
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Microfilament Proteins
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Sulfites
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Tumor Necrosis Factor-alpha
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Interleukin-4
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5-Methylcytosine
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Interferon-gamma
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Cytosine
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DNA Methyltransferase 3A
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Leukocyte Common Antigens
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Adenine
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Thymine