The enhancer HS2 critically regulates GATA-3-mediated Il4 transcription in TH2 cells
The enhancer HS2 critically regulates GATA-3-mediated Il4 transcription in TH2 cells
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DOI：
10.1038/ni.1966
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发表时间：
2011-01-01
影响因子：
30.5
通讯作者：
Kubo, Masato
中科院分区：
文献类型：
--
作者：
Tanaka, Shinya;Motomura, Yasutaka;Kubo, Masato
GATA-3是T辅助2型2（t（h）2）分化的主调节器。但是，GATA-3介导的t（H）2谱系承诺的分子基础知之甚少。在这里，我们将位于白介素4基因座（IL4）的第二个内含子中的DNase I-高敏感位点2（HS2）元素作为严格控制GATA-3结合的关键增强子。缺乏HS2的小鼠在哮喘反应和IL-4的产生中显示出重大损害，但没有其他T（H）2个细胞因子。 HS2缺陷型T细胞中GATA3的过表达未能恢复IL4表达。 HS2缺失损害了在lys4处组蛋白H3的三甲基化，而在lys9和lys9和lys14中，组蛋白H3在IL4基因座中的乙酰化。我们的结果表明，HS2是GATA-3在调节IL4基因座的染色体修饰方面的靶标，并且与IL5和IL13基因座无关。
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.