Genomics based approach for allergic disorderand development of innovative therapeutic strategy

幼稚的CD4 T细胞分化为辅助性T细胞的两个主要亚群，Th1和Th2，这是基于它们的非重叠细胞因子谱和免疫调节功能来定义的。Th1细胞分泌IFN-γ和TNF-α，负责细胞介导的免疫和对细胞内病原体的保护，而Th2细胞产生IL-4、IL-5、IL-6、IL-10和IL-13，介导体液免疫和对蠕虫感染的保护。小鼠Th2细胞因子基因座包含Il4、Il5、Il13以及组成性表达的Rad50和Kif3a基因，其基因座组成在哺乳动物中保守性较好。Th2细胞因子的表达受到顺式作用调控元件上转录许可和抑制染色质结构的遗传调控，这一点已经通过检测DNaseI超敏（HS）位点和组蛋白修饰实验证实。在鼠标Th2轨迹,Il4转录是由元素映射到保守序列1 (HSS1和HSS2 ... 更多的 ), 位于使用Il13 Il4, HS0,位于5”HS1 Il4地区,位于启动子区域,那么HS2和HS3在第二个外显子,HS5a HS5,位于3 ' Il4。Il13基因座包含两个启动子区域，HS1和HS2。HS1是近端启动子HS2上游的保守的GATA-3响应元件（CGRE）。在种系缺失这些调节区域的小鼠中，对IL-4调节元件的研究仍然留下了每个元件是否调节IL-4转录或Th2分化的问题。我们的研究表明，IL-4位点上的HS2是一个关键的GATA-3结合位点，调节谱系特异性IL-4的表达。HS2的缺失显著损害了Il4位点上H3K9/K14乙酰化的维持和H3K4甲基化的开始，这两者都是转录允许性所必需的，导致Il4转录缺失。GATA-3过表达不能重建这些缺陷。我们发现HS2作为GATA-3介导的Il4位点表观遗传修饰的特异性靶点，是一个不可或缺的增强子。因此，我们发现了GATA-3蛋白调控Th2细胞因子基因的新途径。少

Naive CD4 T cells differentiate into two major subsets of helper T cells, Th1 and Th2, which are defined based on their non-overlapping cytokine profiles and immunoregulatory functions. Th1 cells secrete IFN-γ and TNF-α and are responsible for cell-mediated immunity and protection against intracellular pathogens, whereas Th2 cells produce IL-4, IL-5, IL-6, IL-10, and IL-13, and mediate humoral immunity and protection against helminthic infection. The mouse Th2 cytokine locus contains Il4, Il5, Il13, and the constitutively expressed Rad50 and Kif3a genes, and the locus composition is well conserved in mammals. Th2 cytokine expression is heritably regulated by transcriptionally permissive and repressive chromatin structure at cis-acting regulatory elements, which have been experimentally identified by the detection of DNaseI hypersensitive(HS) sites and histone modifications. In the mouse Th2 locus, Il4 transcription is regulated by elements that map to conserved sequence 1(HSS1 and HSS2 … More ), located between Il13 and Il4, HS0, located in the 5' region of Il4, HS1, located in the promoter region, HS2 and HS3 in the second exon, and HS5a and HS5, located 3' of Il4. The Il13 locus contains two promoter regions, HS1 and HS2. HS1 is the conserved GATA-3 response element(CGRE) upstream of the proximal promoter, HS2. Studies of IL-4 regulatory elements in mice with a germline deletion of these regulatory regions still leave open the question of whether each element regulates Il4 transcription or Th2 differentiation. Our study demonstrates that HS2 in the Il4 locus is a critical GATA-3 binding site that regulates lineage specific IL-4 expression. Deletion of HS2 markedly impaired maintenance of H3K9/K14 acetylation and the onset of H3K4 methylation on the Il4 locus, both of which are required for transcriptional permissibility, leading to the lack of Il4 transcription. GATA-3 overexpression failed to reconstitute these defects. We found that HS2, as a specific target of the GATA-3 mediated epigenetic modification on the Il4 locus, is an indispensable enhancer. Therefore, we found a novel regulation of Th2 cytokine genes by GATA-3 protein. Less