Chen Yung-Che, Chao Tung-Ying, Leung Sum-Yee, Chen Chung-Jen, Wu Chao-Chien, Fang Wen-Feng, Wang Yi-Hsi, Chang Huang-Chih, Wang Ting-Ya, Lin Yong-Yong, Zheng Yi-Xin, Lin Meng-Chih, Hsiao Chang-Chun
Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of MedicineKaohsiung, Taiwan.
Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial HospitalTaiwan.
Am J Transl Res. 2017 Apr 15;9(4):1943-1955. eCollection 2017.
The aim of this study is to determine the roles of global histone acetylation (Ac)/methylation (me), their modifying enzymes, and gene-specific histone enrichment in active pulmonary tuberculosis (TB) disease. Global histone H3K27me3, H3K27me2, H3K9me3, H3K9Ac, and H3K14Ac expressions, and their modifying enzyme expressions, including KDM1A, KDM6B, EZH2, HDAC1, and HDAC2, were assessed in blood leukocytes from 81 patients with active pulmonary TB disease and 44 matched healthy subjects (HS). , , , and -specific histone enrichment of peripheral blood mononuclear cells was measured by chromatin immunoprecipitation method. We found that Global H3K14Ac was decreased and H3K27me2 was increased in TB patients as compared with that in HS. TB patients with low H3K14Ac had lower one-year survival. Global H3K27me3 was increased in TB patients with high bacterial burden, or systemic symptoms as compared with that in those without the attribute or HS. HDAC1 gene/protein expressions were increased in TB patients as compared with that in HS, whereas KDM6B gene/protein expressions were decreased. Global H3K27me2, HDAC1 and KDM6B protein expressions were all reversed to normal after 6-month anti-TB treatment. promoter-specific H3K14Ac and promoter-specific H3K27me2 enrichment were all decreased in 10 TB patients as compared with that in 10 HS. Among them, -specific H3K27me2 enrichment was reversed to normal after treatment, while the other 4 remained depressed. In conclusions, H3K14 hypoacetylation and H3K27 hypermethylation play a role in the development of active pulmonary TB disease or its clinical phenotypes, probably through up-regulation of HDAC1 and down-regulation of KDM6B, respectively.
本研究的目的是确定整体组蛋白乙酰化（Ac）/甲基化（me）、其修饰酶以及基因特异性组蛋白富集在活动性肺结核（TB）疾病中的作用。评估了81例活动性肺结核患者和44例匹配的健康受试者（HS）血液白细胞中整体组蛋白H3K27me3、H3K27me2、H3K9me3、H3K9Ac和H3K14Ac的表达，以及它们的修饰酶表达，包括KDM1A、KDM6B、EZH2、HDAC1和HDAC2。通过染色质免疫沉淀法测量外周血单核细胞的基因特异性组蛋白富集。我们发现，与HS相比，肺结核患者的整体H3K14Ac降低，H3K27me2升高。H3K14Ac水平低的肺结核患者一年生存率较低。与没有该特征的患者或HS相比，细菌负荷高或有全身症状的肺结核患者整体H3K27me3升高。与HS相比，肺结核患者HDAC1基因/蛋白表达增加，而KDM6B基因/蛋白表达降低。6个月抗结核治疗后，整体H3K27me2、HDAC1和KDM6B蛋白表达均恢复正常。与10例HS相比，10例肺结核患者的启动子特异性H3K14Ac和启动子特异性H3K27me2富集均降低。其中，治疗后基因特异性H3K27me2富集恢复正常，而其他4个仍处于低水平。总之，H3K14低乙酰化和H3K27高甲基化可能分别通过上调HDAC1和下调KDM6B在活动性肺结核疾病的发生发展或其临床表型中起作用。
