title: Differential patterns of methylation of the IFN-gamma promoter at CpG and non-CpG sites underlie differences in IFN-gamma gene expression between human neonatal and adult CD45RO- T cells.
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.
authors.affiliation: TVW Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, Perth, Western Australia, Australia.
authors.forename: Gregory P
authors.initials: GP
authors.lastname: White
authors.forename: Paul M
authors.initials: PM
authors.lastname: Watt
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Holt
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Holt
mesh_terms: D044503:5-Methylcytosine; D000225:Adenine / Q000378:metabolism; D000328:Adult; D017252:CD3 Complex / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002135:Calcium-Binding Proteins; D003001:Cloning, Molecular; D018899:CpG Islands / Q000187:drug effects / Q000276:immunology*; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018900:Dinucleotide Repeats / Q000276:immunology; D005312:Fetal Blood / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism*; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000096:biosynthesis*; D008840:Microfilament Proteins; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000276:immunology*; D017422:Sequence Analysis, DNA; D013447:Sulfites / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*; D013941:Thymine / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C112986:AIF1 protein, human; D017252:CD3 Complex; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; C000717967:DNMT3A protein, human; D008840:Microfilament Proteins; D013447:Sulfites; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D044503:5-Methylcytosine; D007371:Interferon-gamma; D003596:Cytosine; D000090205:DNA Methyltransferase 3A; D017493:Leukocyte Common Antigens; D000225:Adenine; D013941:Thymine