The direct methylation of CpG islands of genomic DNA is another well-defined epigenetic mechanism to regulate gene expression. In general, hypermethylation is associated with gene repression, while hypomethylation is correlated with gene expression (Refaeli et al. 2002). Early studies on the methylation status of a particular CpG site at position -53 in the proximal IFN-y promoter, revealed it to be predictive of Th1 and Th2 cells' ability to transcribe the ifng gene (Young et al. 1994). This has been corroborated by other studies indicating the IFN-y promoter CpG site exists in a hypermethylated state in Th2 cells but is hypo-methylated in IFN-y-expressing cell populations such as Th1 cells, memory CD8 cells, and NK cells (Fitzpatrick et al. 1998, 1999; Jones and Chen 2006; Tato et al. 2004; Winders et al. 2004; Yano et al. 2003). In addition, methylation of CpA residues in the IFN-y promoter also correlate with IFN-y expression patterns (White et al. 2002). Interestingly, the coding region of the ifng gene is also a target of DNA methylation, as hypermethylation patterns have been observed in naïve CD8+ T cells, naïve CD4+ T cells, and thymocyte precursors (Jones and Chen 2006). Upon T cell activation, however, the ifng gene undergoes a rapid loss of DNA methylation, coinciding with the ability of ifng to be transcribed (Kersh et al. 2006; Northrop et al. 2006). The process of transferring methyl groups is controlled by a family of DNA methyltransferases and deletion of one such member, DNA methyltransferase 1 (Dnmt1), results in augmented levels of IFN-y in Th1 cells (Lee et al. 2001). Overall, it is clear that active methylation/demethylation of the IFN-y promoter and gene is a critical step in the competency of IFN-y to be expressed within the lymphoid compartment.
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