DNA methylation is involved in programming cell type specific gene expression during development [33]. Consistent with this developmental role of DNA methylation, it is involved in naive CD4+ T cells differentiation into Th1 and Th2 cells [34], [35]. The Th2 cytokine locus (IL-4-IL-13-Rad50-IL-5 locus) expressed in Th2 and the IFNγ locus expressed in Th1, undergo chromatin remodeling and DNA demethylation during differentiation ([35] and [36] for review). DNA methylation regulates cytokine gene expression (IL-1α [37], IL-6 [38], IL-8 [39], IL-10 [40] and IL-4 [36]) as well as the expression of the transcription factors (TF) that regulate cytokine expression (NFAT5 [41], STAT6 [42] and STAT1 [43]). TFs are also involved in epigenetic reprogramming of their cytokine targets. For example, STATs are required for maintenance of histone acetylation states in the IL-4 and IFNγ locus [44] and establishment of histone acetylation and DNA demethylation in IL-4 locus requires the presence of STAT6 [44], [45].
