Chromatin landscape dynamics of the Il4-Il13 locus during T helper 1 and 2 development

II4 and II13 encode the canonical T helper 2 (T(H)2) cytokines responsible both for promoting immune responses against extracellular pathogens and, when misregulated, causing allergic and autoimmune disease. The expression potential of these genes undergoes developmentally programmed repression and enhancement during commitment of naive CD4(+) T cells to the mature T helper 1 (T(H)1) and T(H)2 fates, respectively. Thus, like the globin locus, the T(H)2 cytokine locus provides a highly tractable system to study a developmental fate choice leading to alternative transcriptional states of either silence or permissivity. We used quantitative chromatin immunoprecipitation and RT-PCR to correlate changes in the transcriptional states of II4 and II13 with markers of permissive chromatin across the II4-II13 locus in naive CD4(+) T cells undergoing T(H)1 and T(H)2 differentiation. We provide evidence that DNasel hypersensitive site V in the II4 3' enhancer is the likely target for signals maintaining II4 and II13 transcriptional permissivity in naive cells. We also demonstrate rapid acquisition of differences in H3 acetylation between T(H)1- and T(H)2-primed cells, indicating a developmentally early role for cytokine signaling in the process of T-H cell fate determination. Finally, we show that transcriptional repression correlates with the disappearance of permissive H3 modifications from everywhere in the II4-II13 locus except hypersensitive site IV, suggesting a critical role for this element in the maintenance of transcriptional repression. Our findings are consistent with a progressive regulatory element activation/deactivation model of T(H)1/T(H)2 development.