Figure 4.

Model of methylation dynamics at the Cd4 locus during lineage commitment. The Cd4 locus is hypermethylated in double-positive (DP) thymocytes; as MHC class II selected cells downregulate CD8 to become CD4SP cells, the locus undergoes active demethylation presumably through iterative oxidation via ten eleven translocation (TET) enzymes. T helper inducing POZ/Krueppel-like factor (Thpok), which binds to S4 late during positive selection, partially contributes to the demethylation process. In the absence of E4_P, the locus remains hypermethylated in CD4SP cells and resembles the methylation profile of CD8SP cells. Thus, E4_P mediates demethylation of the locus, perhaps in cooperation with E4_M following the selection by MHC class II molecules. In CD8SP cells, which undergo selection for MHC class I interaction, the Cd4 locus remains hypermethylated (with addition of a few novel methyl-CpGs). However, in the absence of S4, the locus undergoes demethylation similarly to CD4SP thymocytes, indicating that S4 potentially inhibits Cd4 demethylation by antagonizing ten eleven translocation (TET)-mediated demethylation.