Figure 3.

Dynamic Cd4 regulation during T cell development in the thymus. In double-negative (DN) thymocytes, Cd4 expression is repressed through S4, which may interact with the E4p enhancer, potentially preventing it from activating the Cd4 promoter. This interaction could be mediated via Runx1, which binds to S4 and associates with AP4 at E4_P, possibly through chromatin looping (see text). Nucleosome remodeling complexes such as the SWI/SNF-like Brg/Brahma-associated factor (BAF) complex are thought to regulate accessibility to S4 to promote silencing. The Cd4 locus in DN thymocytes contains high levels of DNA methylation and lacks high levels of histone acetylation. In double-positive (DP) thymocytes, Cd4 expression is upregulated through E4_P, potentially due to changes in conformation of the locus (see text). E4_P serves as the recruitment site for numerous transcription factors including HEB, E2A, Tcf1, and lymphoid enhancer factor 1. The ATPase subunit of the nucleosome remodeling and deacetylase complex, mi-2β, is a positive regulator of Cd4 expression, possibly through the recruitment of histone acetyltransferases (HATs) to either E4_P or S4. The locus acquires H3Ac and H3K4 trimethylation (H3K4Me3) at S4, but DNA methylation remains high (see Figure 4). In CD8SP cells, Cd4 expression is repressed through the transcription factor Runx3 and Tcf1 binding to S4. The locus acquires some additional DNA methylation and silencing histone marks H3K9Me3 and H3K27Me3. In CD4SP cells, E4_M controls Cd4 potentially in a cooperative manner with E4_P. S4 is bound by the CD4⁺ lineage commitment factor T helper inducing POZ/Krueppel-like factor (Thpok), which antagonizes activity of Runx complexes. The locus undergoes active demethylation and is thus hypomethylated in CD4SP cells relative to all other stages of T cell development (see Figure 4).