Morinobu Akio, Kanno Yuka, O'Shea John J
Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, NIAMS, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Biol Chem. 2004 Sep 24;279(39):40640-6. doi: 10.1074/jbc.M407576200. Epub 2004 Jul 26.
To better understand the control of T helper (TH) 1-expressed genes, we compared and contrasted acetylation and expression for three key genes, IFNG, TBET, and IL18RAP and found them to be distinctly regulated. The TBET and the IFNG genes, but not the IL18RAP gene, showed preferential acetylation of histones H3 and H4 during TH1 differentiation. Analysis of acetylation of specific histone residues revealed that H3(Lys-9), H4(Lys-8), and H4(Lys-12) were preferentially modified in TH1 cells, suggesting a possible contribution of acetylation of these residues for induction of these genes. On the other hand, the acetylation of IL18RAP gene occurred both in TH1 and TH2 cells the similar kinetics and on the same with residues, demonstrating that selective histone acetylation was not universally the case for all TH1-expressed genes. Histone H3 acetylation of IFNG and TBET genes occurred with different kinetics, however, and was distinctively regulated by cytokines. Interleukin (IL)-12 and IL-18 enhanced the histone acetylation of the IFNG gene. By contrast, histone acetylation of the TBET gene was markedly suppressed by IL-4, whereas IL-12 and IL-18 had only modest effects suggesting that histone acetylation during TH1 differentiation is a process that is regulated by various factors at multiple levels. By treating Th2 cells with a histone deacetylase inhibitor, we restored histone acetylation of the IFNG and TBET genes, but it did not fully restore their expression in TH2 cells, again suggesting that histone acetylation explains one but not all the aspects of TH1-specific gene expression.
为了更好地理解辅助性T细胞（TH）1表达基因的调控机制，我们比较并对比了三个关键基因IFNG、TBET和IL18RAP的乙酰化和表达情况，发现它们受到不同的调控。在TH1分化过程中，TBET基因和IFNG基因而非IL18RAP基因，显示出组蛋白H3和H4的优先乙酰化。对特定组蛋白残基乙酰化的分析表明，H3（赖氨酸-9）、H4（赖氨酸-8）和H4（赖氨酸-12）在TH1细胞中优先被修饰，这表明这些残基的乙酰化可能对这些基因的诱导有贡献。另一方面，IL18RAP基因的乙酰化在TH1和TH2细胞中以相似的动力学发生在相同的残基上，这表明选择性组蛋白乙酰化并非所有TH1表达基因的普遍情况。然而，IFNG和TBET基因的组蛋白H3乙酰化以不同的动力学发生，并且受到细胞因子的独特调控。白细胞介素（IL）-12和IL-18增强了IFNG基因的组蛋白乙酰化。相比之下，IL-4显著抑制了TBET基因的组蛋白乙酰化，而IL-12和IL-18的影响较小，这表明TH1分化过程中的组蛋白乙酰化是一个受多种因素在多个水平调控的过程。通过用组蛋白去乙酰化酶抑制剂处理Th2细胞，我们恢复了IFNG和TBET基因的组蛋白乙酰化，但并未完全恢复它们在TH2细胞中的表达，这再次表明组蛋白乙酰化解释了TH1特异性基因表达的一个方面而非全部。
