Epigenetic regulation of beta2-adrenergic receptor expression in TH1 and TH2 cells

We showed previously that murine naive CD4+ T cells and TH1 cell clones express the beta2-adrenergic receptor (β2AR), while TH2 cell clones do not. We report here that naive CD4+ T cells that differentiated for 1-5 days under TH1 driving conditions increased β2AR gene expression, while cells cultured under TH2 driving conditions decrease β2AR gene expression. Chromatin immunoprecipitation revealed that the increase in β2AR gene expression in TH1 cells is mediated by an increase in histone 3 (H3) and H4 acetylation, as well as an increase in histone 3 lysine 4 (H3K4) methylation. Conversely, the decrease in β2AR gene expression in TH2 cells is mediated by a decrease in H3 and H4 acetylation and a decrease in H3K4 methylation, as well as an increase H3K9 and H3K27 methylation. The histone changes could be detected as early as 3 days of differentiating conditions. Genomic bisulfite sequencing showed that the level of methylated CpG dinucleotides within the promoter of the β2AR gene was increased in TH2 cells as compared to naive and TH1 cells. Collectively, these results suggest that epigenetic mechanisms mediate maintenance and repression, respectively, of the β2AR gene expression in TH1- and TH2-driven cells, providing a potential mechanism by which the level of β2AR expression might be modulated pharmacologically within immune cells and other cell types in which the expression profile may change during a disease process.