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  • The EMBO Journal (2006) 25, 2443 - 2452
  • doi:10.1038/sj.emboj.7601148

Published online: 25 May 2006

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

Brendan Jones and Jianzhu Chen

  1. Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA

Correspondence to:

Jianzhu Chen, Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Tel: +1 617 258 6173; Fax: +1 617 258 6172; E-mail: jchen@mit.edu

Received 7 November 2005; Accepted 25 April 2006

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.

  • Keywords:

    • factor binding,
    • IFN-gamma promoter,
    • methylation,
    • T helper cells,
    • transcription