Arsenic Trioxide Reduces Global Histone H4 Acetylation at Lysine 16 through Direct Binding to Histone Acetyltransferase hMOF in Human Cells.
Arsenic Trioxide Reduces Global Histone H4 Acetylation at Lysine 16 through Direct Binding to Histone Acetyltransferase hMOF in Human Cells.
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三氧化二砷通过直接结合人体细胞中的组蛋白乙酰转移酶 hMOF 来减少赖氨酸 16 处的整体组蛋白 H4 乙酰化
DOI：
10.1371/journal.pone.0141014
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Jin J
中科院分区：
文献类型：
--
作者：
Liu D;Wu D;Zhao L;Yang Y;Ding J;Dong L;Hu L;Wang F;Zhao X;Cai Y;Jin J
组蛋白翻译后修饰可遗传地调节参与大多数细胞生物学过程的基因表达。实验研究表明，组蛋白修饰的改变通过改变染色质结构来影响基因表达，从而引起细胞对环境影响的各种反应。砷（As）是一种天然存在的元素和环境污染物，是一种公认的人类致癌物。近年来，越来越多的证据表明，砷介导的表观遗传机制可能参与其毒性和致癌性，但这是如何发生的仍然不清楚。在这里，我们提出的证据表明，作为诱导的全球组蛋白H4 K16乙酰化（H4 K16 ac）部分是由于直接的物理相互作用之间的作为和组蛋白乙酰转移酶（HAT）hMOF（人类男性缺席的第一）蛋白，导致hMOF HAT活性的损失。我们的数据表明，在暴露于三氧化二砷（As 2 O3）的HeLa或HEK 293 T细胞中，整体H4 K16 ac表达下降，脱乙酰转移酶HDAC 4表达增加。然而，HDAC 4的缺失并不影响整体H4 K16 ac，并且在暴露于As 2 O3的细胞中不能提高H4 K16 ac，这表明HDAC 4可能不直接参与组蛋白H4 K16去乙酰化。使用作为固定化琼脂糖，我们证实，作为直接结合hMOF，这种相互作用的竞争性抑制游离As 2 O3。MAIDI-TOF质谱和紫外吸收光谱证实了As与C2CH锌指肽的直接相互作用。在体外HAT试验中，As 2 O3直接抑制hMOF活性。hMOF的过表达不仅能增强对砷的抗性，降低砷的毒性，而且能有效地逆转砷暴露引起的H4 K16 ac的降低。这些数据为阐明砷的毒性机制提供了理论依据。
Histone post-translational modification heritably regulates gene expression involved in most cellular biological processes. Experimental studies suggest that alteration of histone modifications affects gene expression by changing chromatin structure, causing various cellular responses to environmental influences. Arsenic (As), a naturally occurring element and environmental pollutant, is an established human carcinogen. Recently, increasing evidence suggests that As-mediated epigenetic mechanisms may be involved in its toxicity and carcinogenicity, but how this occurs is still unclear. Here we present evidence that suggests As-induced global histone H4K16 acetylation (H4K16ac) partly due to the direct physical interaction between As and histone acetyltransferase (HAT) hMOF (human male absent on first) protein, leading to the loss of hMOF HAT activity. Our data show that decreased global H4K16ac and increased deacetyltransferase HDAC4 expression occurred in arsenic trioxide (As2O3)-exposed HeLa or HEK293T cells. However, depletion of HDAC4 did not affect global H4K16ac, and it could not raise H4K16ac in cells exposed to As2O3, suggesting that HDAC4 might not directly be involved in histone H4K16 de-acetylation. Using As-immobilized agarose, we confirmed that As binds directly to hMOF, and that this interaction was competitively inhibited by free As2O3. Also, the direct interaction of As and C2CH zinc finger peptide was verified by MAIDI-TOF mass and UV absorption. In an in vitro HAT assay, As2O3 directly inhibited hMOF activity. hMOF over-expression not only increased resistance to As and caused less toxicity, but also effectively reversed reduced H4K16ac caused by As exposure. These data suggest a theoretical basis for elucidating the mechanism of As toxicity.