Hypothesis Environmental regulation of 5-hydroxymethyl-cytosine by oxidative stress
Hypothesis Environmental regulation of 5-hydroxymethyl-cytosine by oxidative stress
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DOI：
10.4161/epi.6.7.16461
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发表时间：
2011-07-01
期刊：
影响因子：
3.7
通讯作者：
Ruden, Douglas M.
中科院分区：
文献类型：
--
作者：
Chia, Nancy;Wang, Luan;Ruden, Douglas M.
许多环境毒素，如重金属、空气颗粒物和臭氧，可诱导氧化应激，降低NADH和NADPH的水平，这些辅因子可以驱动合成代谢生化反应，并提供对抗氧化应激的还原能力。最近发现，将DNA中的5-甲基胞嘧啶(5-MC)氧化为5-羟甲基胞嘧啶(5-HMC)的Ten-11易位(Tet)蛋白家族成员在高氧条件下被α-酮戊二酸(α-KG)激活，α-酮戊二酸是柠檬酸循环中有氧代谢产生的辅因子。Tet、Jumonji家族的组蛋白去甲基酶和高氧条件下HIF1α的抑制物Pro羟基酶都需要α-KG作为辅因子才能激活。HIF1α和Tet蛋白似乎具有相反的功能，它们影响人类生活的几个方面，包括细胞生长调节、胚胎干细胞维持、细胞分化和肿瘤发生。新陈代谢在调节全球DNA甲基化和染色质组织中的作用最近得到了生物医学研究界的更多关注。本文将讨论Tet激活的可能作用以及环境应激对5-HMC和5-MC水平的调节。我们还将讨论特定基因启动子上的5-HMC和5-MC水平如何成为暴露于环境毒素的有用生物标志物。
Many environmental toxins, such as heavy metals, air particles and ozone, induce oxidative stress and decrease the levels of NADH and NADPH, cofactors that drive anabolic biochemical reactions and provide reducing capacity to combat oxidative stress. Recently, it was found that the Ten-eleven translocation (TET) protein family members, which oxidize 5-methyl-cytosine (5-mC) to 5-hydroxymethyl-cytosine (5-hmC) in the DNA, were found to be activated under high oxygen conditions by alpha ketoglutarate (alpha-KG), a cofactor produced by aerobic metabolism in the citric acid cycle. TET, Jumonji-family histone demethylases and prolylhydroxylase, a repressor of HIF1 alpha under high oxygen conditions, all require alpha-KG as a cofactor for their activation. HIF1 alpha and TET proteins, which appear to have opposing functions, impact several aspects of human life, including cell growth regulation, embryonic stem cell maintenance, cell differentiation and tumorigenesis. The role of metabolism on the regulation of global DNA methylation and chromatin organization has recently gained greater attention from the biomedical research community. This article will discuss the possible role of TET activation and the regulation of 5-hmC and 5-mC levels in response to environmental stress. We will also discuss how 5-hmC and 5-mC levels at the promoters of specific genes might be a useful biomarker for exposure to environmental toxins.