Regulation of macrophage cyclooxygenase-2 gene expression by modifications of histone H3
Regulation of macrophage cyclooxygenase-2 gene expression by modifications of histone H3
复制标题
DOI：
10.1152/ajplung.00338.2003
复制
发表时间：
2004-05-01
影响因子：
4.9
通讯作者：
Christman, JW
中科院分区：
文献类型：
--
作者：
Park, GY;Joo, M;Christman, JW
在巨噬细胞中，参与调节环氧化酶2（考克斯-2）表达的转录因子，包括NF-κ B，与含有组蛋白乙酰转移酶（HAT）酶复合物的p300相互作用。染色质结构受修饰酶（包括HAT）调节，并通过组蛋白修饰在真核基因调控中起重要作用。我们推测，与组蛋白H3的磷酸化和乙酰化相关的染色质结构的变化与巨噬细胞中考克斯-2启动子中的关键DNA结合序列基序相关，有助于考克斯-2基因的激活。丁酸钠（NaBT）是一种短链脂肪酸，具有组蛋白脱乙酰基转移酶抑制活性。我们的数据表明，NaBT加重LPS诱导的考克斯-2基因的表达在转录水平，即使NaBT单独不诱导考克斯-2基因的表达。使用染色质免疫沉淀试验，我们发现，共刺激RAW 264.7细胞与NaBT和LPS协同增加考克斯-2基因的表达，通过乙酰化和磷酸化组蛋白H3的启动子位点。我们的数据表明，NaBT通过MAP激酶依赖性增加组蛋白H3在考克斯-2启动子位点的磷酸化和乙酰化来增强LPS诱导的考克斯-2基因表达。这些数据表明，组蛋白H3的翻译后修饰对巨噬细胞的考克斯-2基因表达有重要影响。
Some transcription factors involved in the regulation of cyclooxygenase 2 (COX-2) expression in macrophage, including NF-kappaB, interact with p300, which contains histone acetyltransferase ( HAT) enzyme complex. Chromatin structure is regulated by modifying enzymes, including HAT, and plays an important role in eukaryotic gene regulation through histone modification. We hypothesized that changes in chromatin structure related to phosphorylation and acetylation of histone H3 adjacent to key DNA binding sequence motif in the COX-2 promoter contribute to COX-2 gene activation in macrophages. Sodium butyrate (NaBT) is a short-chain fatty acid that possesses histone deacetyltransferase-inhibiting activity. Our data show that NaBT accentuates LPS-induced COX-2 gene expression at a transcriptional level, even though NaBT alone does not induce the COX-2 gene expression. Using a chromatin immunoprecipitation assay, we showed that costimulation of RAW 264.7 cells with NaBT and LPS synergistically increases COX-2 gene expression through both acetylation and phosphorylation of histone H3 at the promoter site. Our data show that NaBT accentuates LPS-induced COX-2 gene expression through MAP kinase-dependent increase of phosphorylation and acetylation of histone H3 at the COX-2 promoter site. These data indicate that posttranslational modification of histone H3 has a major effect on COX-2 gene expression by macrophages.