HISTONE MODIFICATIONS OF NOTCH1 PROMOTER AFFECT LUNG CD4+ T CELL DIFFERENTIATION IN ASTHMATIC RATS
HISTONE MODIFICATIONS OF NOTCH1 PROMOTER AFFECT LUNG CD4+ T CELL DIFFERENTIATION IN ASTHMATIC RATS
复制标题
Notch1启动子的组蛋白修饰影响哮喘大鼠肺CD4 T细胞分化
DOI：
10.1177/039463201302600210
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发表时间：
2013-04-01
影响因子：
3.5
通讯作者：
Guo, X-J
中科院分区：
文献类型：
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作者：
Cui, Z-L;Gu, W.;Guo, X-J
哮喘是一种气道炎症性疾病，目前治疗哮喘的方法是控制炎症。Notch信号通路与T细胞失衡有关。本研究旨在探讨Notch 1启动子在正常和哮喘肺CD 4（+）T细胞中的组蛋白修饰。染色质免疫沉淀分析显示，哮喘患者肺CD 4（+）T细胞Notch 1基因启动子的总113、H4、位点特异性H3 K9、H3 K14、H3 K27、H3 K18、H4 K16的乙酰化水平和H3 K4、H3 K79的三甲基化水平较对照组显著升高，与P300升高相关，HDAC 1、HDAC 2活性降低。在组蛋白乙酰转移酶的有效抑制剂Garcinol干预后，哮喘肺CD 4（+）T细胞中的HAT活性显著降低，Notch 1和hes-1表达的增加被逆转。Notch 1基因启动子的总H3 ac、H4 ac、位点特异性H3 K9 ac、H3 K14 ac、H3 K27 ac、H3 K18 ac、H4 K16 ac和H3 K79 me 3水平显著降低，H3 K4 me 3、H3 K9 me 3、H4 K20 me 3水平差异不显著。我们进一步研究了GAR对哮喘参数的抑制作用。结果表明，GAR治疗后IL-4、IL-5和IL-13水平明显降低，IFN-γ水平有小幅逆转趋势。NF-κ B和AP-1的表达明显降低。这些结果表明哮喘与Notch 1启动子表观遗传状态的改变有关，包括组蛋白乙酰化和甲基化异常，GAR可能在哮喘治疗中有应用价值。
Asthma is an inflammatory disease of the airways, and the current treatment in managing asthma is the control of inflammation. Notch signaling pathway has been linked to T-cell imbalance. The present study aimed to explore the histone modifications of Notch1 promoter in normal and asthmatic lung CD4(+) T cells. Chromatin inimunoprecipitation analysis showed that the acetylation levels of total 113, H4, site-specific H3K9, H3K14, H3K27, H3K18, H4K16, and the trimethylation levels of H3K4, H3K79 of Notch1 gene promoter were increased significantly in asthmatic lung CD4(+) T cells compared to the control group, which correlated with increased P300, PCAF activity and decreased HDAC1, HDAC2 activity. After intervention of garcinol, a potent inhibitor of histone acetyltransferases, in asthmatic lung CD4(+) T cells, HAT activity decreased significantly and the increased Notch1 and hes-1 expression was reversed. The total H3ac, H4ac, site-specific H3K9ac, H3K14ac, H3K27ac, H3K18ac, H4K16ac and H3K79me3 levels of Notch1 gene promoter decreased significantly, and the H3K4me3, H3K9me3, H4K20me3 levels had no significant difference. We further investigated the suppressive effects of GAR on asthmatic parameters. Results showed that the levels of IL-4, IL-5 and IL-13 were significantly reduced and a small reverse trend was found in the level of IFN-g after GAR treatment. Furthermore, the expression of NF-kappa B and AP-1 reduced significantly. These results suggest that asthma is associated with changes in the epigenetic status of Notch1 promoter, including abnormal histone acetylation and methylation, and GAR may have applications in the treatment of asthma.