Th1/Th2 cell differentiation and chromatin remodeling of the Th2 cytokine gene locus

Th1/Th2 细胞分化和 Th2 细胞因子基因座的染色质重塑

• 批准号: 14370107
• 负责人: NAKAYAMA Toshinori
• 金额: $ 8.9万
• 依托单位: Chiba University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370107/
• 关键词: Th2 cell; chromatin remodeling; CGRE; ROG; bmi-1; polycomb; histone acetylation; IL-4; ポリコーム遺伝子; Ring1B; Th1; Th2; アレルギー; 気道炎症; Th2サイトカイン; GATA3; リモデリング; Th2サイトカン

Differentiation of naive CD4 T cells into Th2 cells is accompanied by chromatin remodeling including hyperacetylation of histones H3 and H4 in the nucleosomes associated with the IL-4,IL-13 and IL-5 genes. A conserved GATA3 response element (CGRE) containing four GATA consensus sequences was identified 1.6 kbp upstream of the IL-13 gene, corresponding with the 5' border of the Th2-specific histone hyperacetylation region. The CGRE was shown to bind to GATA3, histone acetyl transferase complexes including CBP/p300, and RNA polymerase II. Thus, the CGRE may play a crucial role for GATA3-mediated targeting and downstream spreading of core histone hyperacetylation within the IL-13 and IL-4 gene loci. As for the IL-5 gene locus, CD28-costimulation selectively enhanced histone hyperacetylation through NF-kB activation and subsequent upregulation of GATA3. Chromatin remodeling of type 2 cytokine gene loci occurs also in developing CD8 Tc2 T cells. IL-4 production and histone hyperacetylation in IL-4-associated nucleosomes in developing Tc2 cells were significantly lower than those of Th2 cells, however, cytokine production and histone hyperacetylation of IL-5 and IL-13 genes were equivalent. Developing Tc2 cells expressed lower GATA3 levels and dramatically increased levels of repressor of GATA (ROG). A ROG response element in the IL-13 gene exon 4 displayed Tc2-specific bin4ing of ROG,HDAC1 and HDAC2, and exhibited repression of IL-4 gene activation. Thus, ROG may confer CD8 T cell-specific repression of histone hyperacetylation and activation of the IL-4 gene locus.

幼稚CD 4 T细胞分化为Th 2细胞伴随着染色质重塑，包括与IL-4、IL-13和IL-5基因相关的核小体中组蛋白H3和H4的超乙酰化。在IL-13基因上游1.6kbp处发现了一个保守的GATA 3应答元件（CGRE），该元件含有4个加塔共有序列，对应于Th 2特异性组蛋白高乙酰化区的5'端边界。CGRE显示与GATA 3、组蛋白乙酰转移酶复合物（包括CBP/p300）和RNA聚合酶II结合。因此，CGRE可能在IL-13和IL-4基因座内的核心组蛋白超乙酰化的GATA 3介导的靶向和下游扩散中发挥关键作用。至于IL-5基因位点，CD 28共刺激通过NF-κ B激活和随后的GATA 3上调选择性地增强组蛋白超乙酰化。2型细胞因子基因位点的染色质重塑也发生在发育中的CD 8 Tc 2 T细胞中。在发育中的Tc 2细胞中IL-4产生和IL-4相关核小体中的组蛋白超乙酰化显著低于Th 2细胞，然而，IL-5和IL-13基因的细胞因子产生和组蛋白超乙酰化是相当的。发育中的Tc 2细胞表达较低的GATA 3水平和显著增加的加塔阻遏物（ROG）水平。IL-13基因外显子4中的ROG反应元件显示出ROG、HDAC 1和HDAC 2的Tc 2特异性结合，并显示出对IL-4基因活化的抑制。因此，ROG可以赋予CD 8 T细胞特异性抑制组蛋白超乙酰化和激活IL-4基因座。

项目成果

CD28 costimulation controls histone hyperacetylation of the IL-5 gene locus in developing Th2 cells.

CD28 共刺激控制发育中 Th2 细胞中 IL-5 基因座的组蛋白过度乙酰化。

• 发表时间: 2004
• 期刊: J. Biol. Chem 279・22
• 作者: Inami;M.
• 通讯作者: M.

Kamata, T., Yamashita, M., Kimura, M., Murata, K., Inami M., Shimizu, C., Sugaya, K., Wang C.-R., Taniguchi, M., Nakayama, T.: "src homology 2 domain-containing tyrosine phosphatase SHP-1 controls the development of allergic airway inflammation"J. Clin. I

Kamata, T.、Yamashita, M.、Kimura, M.、Murata, K.、Inami M.、Shimizu, C.、Sugaya, K.、Wang C.-R.、Taniguchi, M.、Nakayama, T.

Ashcroft, G.S., Mills, S.J., Lei, K., Gibbons, L., Burow, M., Jeong, M-J., Taniguchi, M., Horan, M.A., Wahl, S.M., Nakayama, T.: "Estrogen modulates cutaneous wound healing by down-regulating macrophage migration inhibitory factor"J. Clin. Inv.. (in press

Ashcroft, G.S.、Mills, S.J.、Lei, K.、Gibbons, L.、Burow, M.、Jeong, M-J.、Taniguchi, M.、Horan, M.A.、Wahl, S.M.、Nakayama, T.：“雌激素调节皮肤

Impaired contact hypersensitivity in macrophage migration inhibitory factor, MIF-deficient mice.

巨噬细胞迁移抑制因子、MIF 缺陷小鼠的接触超敏反应受损。

• 发表时间: 2003
• 期刊: Eur.J.Immunol. 33
• 作者: Shimizu;T.
• 通讯作者: T.

Preserved IFN-γ production of circulating Vα24 NKT cells in primary lung cancer patients.

原发性肺癌患者中循环 Vα24 NKT 细胞保留了 IFN-γ 的产生。

• 发表时间: 2002
• 期刊: Int.J.Cancer. 102
• 作者: Motohashi;S.
• 通讯作者: S.