Epigenetic regulation of extracellular-superoxide dismutase in human monocytes
Epigenetic regulation of extracellular-superoxide dismutase in human monocytes
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DOI：
10.1016/j.freeradbiomed.2013.04.013
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发表时间：
2013-08-01
影响因子：
7.4
通讯作者：
Adachi, Tetsuo
中科院分区：
文献类型：
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作者：
Kamiya, Tetsuro;Machiura, Masatomo;Adachi, Tetsuo
细胞外超氧化物歧化酶(EC-SOD)是一种主要存在于血管壁中的超氧化物歧化酶同工酶，在正常的氧化还原动态平衡中起着重要作用。我们先前已经证明，在12-O-十四酰佛波醇-13-乙酸酯(TPA)诱导的人单核细胞U937或THP-1细胞分化过程中，EC-SOD的表达显著减少或显著诱导，但其细胞特异性表达和调控机制尚未完全阐明。据报道，表观遗传因素，如DNA甲基化和组蛋白修饰，参与了多种基因调控。在这项研究中，我们研究了表观遗传因素对EC-SOD表达的影响，并发现与U937细胞相比，THP-1细胞中EC-SOD启动子和编码区的DNA甲基化水平较高。此外，DNA甲基转移酶抑制剂5-氮胞苷显著诱导THP-1细胞EC-SOD的表达，表明DNA甲基化在抑制EC-SOD表达中的重要性，但在TPA诱导的THP-1细胞分化过程中，DNA甲基化状态没有改变。另一方面，我们在分化过程中检测到组蛋白H3和H4乙酰化。此外，组蛋白乙酰转移酶抑制剂CPTH2或藤黄酚可显著抑制TPA诱导的EC-SOD的表达。我们还检测了外周血单核细胞中EC-SOD的表观遗传抑制。粒细胞巨噬细胞集落刺激因子(GM-CSF)/粒细胞-CSF处理诱导了这种表达。总之，这些发现提供了新的证据，表明人类单核细胞中细胞特异性和TPA诱导的EC-SOD的表达受DNA甲基化和组蛋白H3和H4乙酰化的调节。(C)2013 Elsevier Inc.保留所有权利。
Extracellular-superoxide dismutase (EC-SOD) is a major SOD isozyme mainly present in the vascular wall and plays an important role in normal redox homeostasis. We previously showed the significant reduction or induction of EC-SOD during human monocytic U937 or THP-1 cell differentiation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), respectively; however, its cell-specific expression and regulation have not been fully elucidated. It has been reported that epigenetic factors, such as DNA methylation and histone modification, are involved in several kinds of gene regulation. In this study, we investigated the involvement of epigenetic factors in EC-SOD expression and determined high levels of DNA methylation within promoter and coding regions of EC-SOD in THP-1 cells compared to those in U937 cells. Moreover, treatment with a DNA methyltransferase inhibitor, 5-azacytidine, significantly induced the expression of EC-SOD in THP-1 cells, indicating the importance of DNA methylation in the suppression of EC-SOD expression; however, the DNA methylation status did not change during THP-1 cell differentiation induced by TPA. On the other hand, we detected histone H3 and H4 acetylation during differentiation. Further, pretreatment with histone acetyltransferase inhibitors, CPTH2 or garcinol, significantly suppressed the TPA-inducible EC-SOD expression. We also determined the epigenetic suppression of EC-SOD in peripheral blood mononuclear cells. Treatment with granulocyte macrophage colony-stimulating factor (GM-CSF)/granulocyte-CSF induced that expression. Overall, these findings provide novel evidence that cell-specific and TPA-inducible EC-SOD expression are regulated by DNA methylation and histone H3 and H4 acetylation in human monocytic cells. (C) 2013 Elsevier Inc. All rights reserved.