Epigenetic mechanisms explain the lineage relationship between Th17, Th1, and iTreg subsets. (A) Whether a particular gene is poised for expression or not is determined by the chromatin structure, as well as histone and DNA methylation states. Trimethylation of histone 3H on lysine 4 (H3K4me3) is considered permissive for gene expression, whereas trimethylation of lysine 27 on histone 3H (H3K27me3) is a marker of gene silencing. In some cases, both states can be found in a gene locus, thus making it susceptible for either expression or negative regulation. (B) Plasticity of Th1, Th17, and iTreg cells is constrained by the epigenetic status of genes encoding for the master transcriptional regulators of polarization and canonical cytokines. Th17 cells display permissive H3K4me3 histone modification over the rorc and il17 genes and bivalent, poised status over loci encoding for tbx21 and foxp3, thus substantiating the relative instability of this subset and its propensity to evolve into Th1 progeny. In contrast, Th1 cells display only repressive H3K27me3 methylation status over gene loci encoding for rorc and Il17, rendering them much more stable. iTregs are another relatively unstable subset that can acquire Th1 or Th17 properties, based on the poised bivalent status of type 1– or type 17–associated genes.
