Inhibition of IFN-γ transcription by site-specific methylation during T helper cell development

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Abstract
Polarization of naïve CD4 T cells into T helper type 2 (TH2) cells is characterized by expression of IL‐4 and silencing of IFN‐γ. Here we show that during TH2 polarization, the DNA methyltransferase Dnmt3a is recruited to the IFN‐γ 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‐γ promoter in T helper type 1 (TH1) cells but not the methylated IFN‐γ promoter in TH2 cells. Furthermore, methylation at the −53 CpG alone is sufficient to inhibit the IFN‐γ 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‐γ transcription in developing TH2 cells by directly inhibiting transcription factor binding.