Genomewide Histone H3 Lysine 9 Acetylation Profiling in CD4+T Cells Revealed Endoplasmic Reticulum Stress Deficiency in Patients with Acute-on-chronic Liver Failure
Genomewide Histone H3 Lysine 9 Acetylation Profiling in CD4+T Cells Revealed Endoplasmic Reticulum Stress Deficiency in Patients with Acute-on-chronic Liver Failure
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DOI：
10.1111/sji.12341
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发表时间：
2015-11-01
影响因子：
3.7
通讯作者：
He, Y.
中科院分区：
文献类型：
--
作者：
Jin, L.;Wang, K.;He, Y.
慢加急性肝衰竭（ACLF）呈现出脓毒症样的免疫麻痹。对于作为先天性和适应性免疫系统主要调节因子的CD4 + T淋巴细胞在ACLF中所起的作用知之甚少。组蛋白H3赖氨酸9（H3K9ac）的乙酰化是一种关键的表观遗传修饰，它紧密控制基因转录。H3K9ac修饰是否以及如何调节ACLF中的CD4 + T细胞仍不清楚。从ACLF患者、慢性乙型肝炎免疫耐受（CHB - T）患者和慢性乙型肝炎免疫活动期（CHB - A）患者中分离外周血单个核细胞（PBMCs）。然后，通过磁珠纯化CD4 + T淋巴细胞，并通过流式细胞术确认其纯度。使用染色质免疫沉淀微阵列分析CD4 + T细胞中H3K9ac的变化，然后通过定量PCR进行确认。通过生物信息学进行全基因组H3K9乙酰化分析。在CHB - A组和ACLF组之间，共有70个基因的H3K9ac修饰存在差异，而在CHB - T组和ACLF组之间，有44个基因的H3K9ac修饰存在差异。聚类算法分析显示ACLF患者呈现出脓毒症样的免疫麻痹。功能分析表明内质网（ER）应激或下游通路相关基因，如BIP、ATF4、PER1、CSNK1D、IRF3、BNIP1、AKT1和UBC，在ACLF中存在差异修饰。我们分析了来自处于三种不同免疫状态（即ACLF、免疫耐受和免疫活动期）的乙肝感染患者的CD4 + T淋巴细胞中的H3K9乙酰化修饰。ACLF呈现出脓毒症样的免疫麻痹。CD4 + T淋巴细胞中的内质网应激归因于ACLF。本研究为揭示ACLF的潜在机制提供了一些有用的线索。
Acute-on-chronic liver failure (ACLF) displayed sepsis-like' immune paralysis. Little is known about the role of CD4+ T lymphocytes, the primary regulator of innate and adopted immune system, played in ACLF. Acetylation of histone H3 lysine 9 (H3K9ac), a key epigenetic modification, tightly controls gene transcription. Whether and how does H3K9ac modification regulate CD4+ T cells in ACLF remains unclear. PBMCs were isolated from patients with ACLF, immune tolerance of chronic hepatitis B (CHB-T) and immune active of chronic hepatitis B (CHB-A). Then, CD4+ T lymphocytes were purified by magnetic microbeads, and the purity was confirmed by flow cytometry. H3K9ac variations were analysed in CD4+ T cells using chromatin immunoprecipitation microarray and then confirmed by quantitative PCR. Whole-genome H3K9 acetylation analyses were conducted by bioinformatics. A total of 70 genes were differently modified in H3K9ac between CHB-A and ACLF groups, while 44 genes were differently modified in H3K9ac between CHB-T and ACLF groups. Clustering algorithm analysis showed patients with ACLF displayed sepsis-like' immune paralysis. Functional analysis showed endoplasmic reticulum (ER) stress, or downstream pathway-related genes, such as BIP, ATF4, PER1, CSNK1D, IRF3, BNIP1, AKT1 and UBC, were differentially modified in ACLF. We profiled H3K9 acetyl modification in CD4+ T lymphocytes from HBV-infected patients with three different immune states, that is ACLF, immune tolerance and immune active phases. ACLF displayed sepsis-like' immune paralysis. ER stress in CD4+ T lymphocytes attributed to ACLF. This study provides some useful clues for revealing the mechanisms underlying ACLF.