Induction of gamma-globin by histone deacetylase inhibitors
Induction of gamma-globin by histone deacetylase inhibitors
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DOI：
10.1182/blood.v90.5.2075
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发表时间：
1997-09-01
期刊：
影响因子：
20.3
通讯作者：
Su, MSS
中科院分区：
文献类型：
--
作者：
McCaffrey, PG;Newsome, DA;Su, MSS
短链脂肪酸丁酸盐已被证明通过诱导γ-珠蛋白基因的表达来提高胎儿血红蛋白（HbF）。丁酸盐对基因表达的调节被认为是通过抑制组蛋白脱乙酰酶来进行的，导致核心组蛋白乙酰化水平升高，这影响染色质结构和转录速率。为了确定组蛋白乙酰化的变化是否对γ-珠蛋白基因的调节至关重要，我们测试了三种有效的和特异性的组蛋白脱乙酰酶抑制剂，环四肽trapoxin和Helminthsporium carbonum毒素（HC毒素），以及抗真菌抗生素阿司他丁A诱导红系细胞中胎儿血红蛋白表达的能力。这些化合物在原代红系细胞培养物和人红白血病（K562）细胞中诱导胎儿血红蛋白。在K562细胞中使用报告构建体的瞬时转染试验中，已经确定了跨越γ-珠蛋白启动子的重复CCAAT盒区域的丁酸盐响应元件，并且我们表明，对trapoxin和resistatin的响应需要相同的启动子区域。γ-珠蛋白启动子的突变分析表明，远端CCAAT盒和3'侧翼序列（CCAATAGCC）对于丁酸盐、trapoxin和阿司他丁的激活至关重要，而近端元件这些结果表明，组蛋白脱乙酰酶的抑制可以通过近端启动子元件导致γ-珠蛋白启动子报告基因构建体的转录激活，并表明丁酸盐通过组蛋白乙酰化的这种变化诱导γ-珠蛋白表达。(C)1997年，美国血液学会。
The short-chain fatty acid butyrate has been shown to elevate fetal hemoglobin (HbF) by inducing expression of the gamma-globin gene, Regulation of gene expression by butyrate is thought to proceed via inhibition of the enzyme histone deacetylase, leading to elevated levels of core histone acetylation which affect chromatin structure and transcription rates. To determine whether changes in histone acetylation are critical for the regulation of the gamma-globin gene, we tested three potent and specific inhibitors of histone deacetylase, the cyclic tetrapeptides trapoxin and Helminthsporium carbonum toxin (HC toxin), and the antifungal antibiotic trichostatin A for their ability to induce fetal hemoglobin expression in erythroid cells. These compounds induced fetal hemoglobin in both primary erythroid cell cultures and human erythroleukemia (K562) cells, A butyrate-responsive element spanning the duplicated CCAAT box region of the gamma-globin promoter has been identified in transient transfection assays using a reporter construct in K562 cells, and we show that the same promoter region is required for response to trapoxin and trichostatin. Mutational analysis of the gamma-globin promoter indicates that the distal CCAAT box and 3' flanking sequence (CCAATAGCC) is critical for activation by butyrate, trapoxin, and trichostatin, whereas the proximal element (CCAATAGTC) plays a less important role, These results show that inhibition of histone deacetylase can lead to transcriptional activation of gamma-globin promoter reporter gene constructs through proximal promoter elements, and suggest that butyrate induces gamma-globin expression via such changes in histone acetylation. (C) 1997 by The American Society of Hematology.