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Inhibition of IFN‐γ transcription by site‐specific methylation during T helper cell development
Author(s) -
Jones Brendan,
Chen Jianzhu
Publication year - 2006
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601148
Subject(s) - biology , transcription factor , transcription (linguistics) , methylation , dna methylation , binding site , genetics , microbiology and biotechnology , gene , gene expression , linguistics , philosophy
Polarization of naïve CD4 T cells into T helper type 2 (T H 2) cells is characterized by expression of IL‐4 and silencing of IFN‐γ. Here we show that during T H 2 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 (T H 1) cells but not the methylated IFN‐γ promoter in T H 2 cells. Furthermore, methylation at the −53 CpG alone is sufficient to inhibit the IFN‐γ promoter‐driven reporter gene expression in a T H 1 cell line. These findings suggest that rapid methylation of the evolutionarily conserved −53 CpG by Dnmt3a may suppress IFN‐γ transcription in developing T H 2 cells by directly inhibiting transcription factor binding.