Inhibition of IFN-gamma transcription by site-specific methylation during T helper cell development.
Polarization of naïve CD4 T cells into T helper type 2 (TH2) cells is characterized by expression of IL-4 and silencing of IFN-gamma. Here we show that during TH2 polarization, the DNA methyltransferase Dnmt3a is recruited to the IFN-gamma promoter and correspondingly the promoter undergoes progressive de novo methylation. Notably, the CpG located at the -53 position becomes methylated rapidly and this methylation inhibits ATF2/c-Jun and CREB transcription factor binding in vitro. In vivo, the same factors bind to the unmethylated IFN-gamma promoter in T helper type 1 (TH1) cells but not the methylated IFN-gamma promoter in TH2 cells. Furthermore, methylation at the -53 CpG alone is sufficient to inhibit the IFN-gamma promoter-driven reporter gene expression in a TH1 cell line. These findings suggest that rapid methylation of the evolutionarily conserved -53 CpG by Dnmt3a may suppress IFN-gamma transcription in developing TH2 cells by directly inhibiting transcription factor binding.
Jones
Brendan
B
Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Chen
Jianzhu
J
D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D018899:CpG Islands; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D011401:Promoter Regions, Genetic; D016176:T-Lymphocyte Subsets; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000502:physiology*; D014158:Transcription, Genetic
D051698:Activating Transcription Factor 2; C497106:Atf2 protein, mouse; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D007371:Interferon-gamma; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A