The enhancer HS2 critically regulates GATA-3-mediated Il4 transcription in T(H)2 cells.
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.
Laboratory for Signal Network, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama, Japan.
Shinya
S
Tanaka
Yasutaka
Y
Motomura
Yoshie
Y
Suzuki
Ryoji
R
Yagi
Hiromasa
H
Inoue
Shoichiro
S
Miyatake
Masato
M
Kubo
D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D019175:DNA Methylation / Q000235:genetics / Q000276:immunology; D003850:Deoxyribonuclease I / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology; D006657:Histones / Q000378:metabolism*; D047668:Inteins / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019076:Transgenes / Q000235:genetics
D050990:GATA3 Transcription Factor; D006657:Histones; D015847:Interleukin-4; D003850:Deoxyribonuclease I