Dynamic Readers for 5-(Hydroxy)Methylcytosine and Its Oxidized Derivatives
Dynamic Readers for 5-(Hydroxy)Methylcytosine and Its Oxidized Derivatives
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DOI：
10.1016/j.cell.2013.02.004
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发表时间：
2013-02-28
期刊：
影响因子：
64.5
通讯作者：
Vermeulen, Michiel
中科院分区：
文献类型：
--
作者：
Spruijt, Cornelia G.;Gnerlich, Felix;Vermeulen, Michiel
泰特蛋白氧化5-甲基胞嘧啶（mC）以产生5-羟甲基（hmC）、5-甲酰基（fC）和5-羧基胞嘧啶（caC）。这些氧化胞嘧啶碱基的确切功能仍然难以捉摸。我们应用定量质谱为基础的蛋白质组学，以确定读者的mC和hmC在小鼠胚胎干细胞（mESC），神经元祖细胞（NPC），和成年小鼠脑组织。这些修饰的阅读器仅部分重叠，并且一些阅读器，如Rfx蛋白，显示出强特异性。相互作用在分化过程中是动态的，例如Klf 4与mC的mESC特异性结合和Uhrf 2与hmC的NPC特异性结合所证明的，表明mC和hmC的特定生物学作用。mC的氧化衍生物在小鼠ES细胞中招募不同的转录调节因子以及大量的DNA修复蛋白，暗示DNA损伤反应是活性DNA去甲基化的主要参与者。
Tet proteins oxidize 5-methylcytosine (mC) to generate 5-hydroxymethyl (hmC), 5-formyl (fC), and 5-carboxylcytosine (caC). The exact function of these oxidative cytosine bases remains elusive. We applied quantitative mass-spectrometry-based proteomics to identify readers for mC and hmC in mouse embryonic stem cells (mESC), neuronal progenitor cells (NPC), and adult mouse brain tissue. Readers for these modifications are only partially overlapping, and some readers, such as Rfx proteins, display strong specificity. Interactions are dynamic during differentiation, as for example evidenced by the mESC-specific binding of Klf4 to mC and the NPC-specific binding of Uhrf2 to hmC, suggesting specific biological roles for mC and hmC. Oxidized derivatives of mC recruit distinct transcription regulators as well as a large number of DNA repair proteins in mouse ES cells, implicating the DNA damage response as a major player in active DNA demethylation.