Role of epigenetic modifications in normal globin gene regulation and butyrate-mediated induction of fetal hemoglobin
Role of epigenetic modifications in normal globin gene regulation and butyrate-mediated induction of fetal hemoglobin
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DOI：
10.1182/blood-2007-02-076091
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发表时间：
2007-11-01
期刊：
影响因子：
20.3
通讯作者：
Atweh, George F.
中科院分区：
文献类型：
--
作者：
Fathallah, Hassana;Weinberg, Rona S.;Atweh, George F.
丁酸盐是组蛋白脱乙酰酶抑制剂的原型，被认为通过诱导表观遗传修饰来重新激活沉默的基因。虽然丁酸盐被证明可以诱导血红蛋白紊乱患者胎儿血红蛋白(HBF)的产生，但这种诱导的机制还没有完全阐明。我们对P-珠蛋白簇的表观遗传构型的研究表明，DNA甲基化和组蛋白H3乙酰化对于调控类β珠蛋白基因的发育阶段特异性表达是重要的，而组蛋白H3和H4的乙酰化似乎对于组织特异性表达的调控是重要的。这些研究表明，DNA甲基化可能对非红系造血细胞中P样珠蛋白基因的沉默起重要作用，但可能不是非造血细胞中P样珠蛋白基因沉默所必需的。此外，我们的研究表明，丁酸暴露导致正常发育转换的真正逆转，从伽马-珠蛋白表达到β-珠蛋白表达。这与组蛋白乙酰化增加和伽马珠蛋白基因的DNA甲基化减少有关，而β-珠蛋白基因的变化则相反。这些研究为表观遗传修饰在珠蛋白基因表达的正常发育和组织特异性调控中的作用以及在丁酸介导的药物诱导HBF产生中的作用提供了强有力的支持。
Butyrate is a prototype of histone deacetylase inhibitors that is believed to reactivate silent genes by inducing epigenetic modifications. Although butyrate was shown to induce fetal hemoglobin (HbF) production in patients with hemoglobin disorders, the mechanism of this induction has not been fully elucidated. Our studies of the epigenetic configuration of the P-globin cluster suggest that DNA methylation and histone H3 acetylation are important for the regulation of developmental stage-specific expression of the beta-like globin genes, whereas acetylation of both histones H3 and H4 seem to be important for the regulation of tissue-specific expression. These studies suggest that DNA methylation may be important for the silencing of the P-like globin genes in nonerythroid hematopoietic cells but may not be necessary for their silencing in nonhematopoietic cells. Furthermore, our studies demonstrate that butyrate exposure results in a true reversal of the normal developmental switch from, gamma- to beta-globin expression. This is associated with increased histone acetylation and decreased DNA methylation of the gamma-globin genes, with opposite changes in the beta-globin gene. These studies provide strong support for the role of epigenetic modifications in the normal developmental and tissue-specific regulation of globin gene expression and in the butyrate-mediated pharmacologic induction of HbF production.