The enhancer HS2 critically regulates GATA-3-mediated Il4 transcription in TH2 cells

The molecular basis of T H 2 lineage commitment is poorly understood. Kubo and colleagues identify the Il4 enhancer HS2 as a target of the transcription factor GATA-3 and show it to be critical for IL-4 production and T H 2 functional commitment. GATA-3 is a master regulator of T helper type 2 (T H 2) differentiation. However, the molecular basis of GATA-3-mediated T H 2 lineage commitment is poorly understood. Here we identify the DNase I–hypersensitive site 2 (HS2) element located in the second intron of the interleukin 4 locus ( Il4 ) as a critical enhancer strictly controlled by GATA-3 binding. Mice lacking HS2 showed substantial impairment in their asthmatic responses and their production of IL-4 but not of other T H 2 cytokines. Overexpression of Gata3 in HS2-deficient T cells failed to restore Il4 expression. HS2 deletion impaired the trimethylation of histone H3 at Lys4 and acetylation of histone H3 at Lys9 and Lys14 in the Il4 locus. Our results indicate that HS2 is the target of GATA-3 in regulating chromosomal modification of the Il4 locus and is independent of the Il5 and Il13 loci.