Methyl-CpG binding domain protein 1 regulates localization and activity of Tet1 in a CXXC3 domain-dependent manner
Methyl-CpG binding domain protein 1 regulates localization and activity of Tet1 in a CXXC3 domain-dependent manner
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DOI：
10.1093/nar/gkx281
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发表时间：
2017-04
影响因子：
14.9
通讯作者：
Peng Zhang;Cathia Rausch;Florian D. Hastert;Boyana Boneva;A. Filatova;Sujit J. Patil;U. Nuber;Yu Gao;Xinyu Zhao;M. C. Cardoso
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文献类型：
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作者：
Peng Zhang;Cathia Rausch;Florian D. Hastert;Boyana Boneva;A. Filatova;Sujit J. Patil;U. Nuber;Yu Gao;Xinyu Zhao;M. C. Cardoso
摘要 胞嘧啶修饰使基因组多样化和结构化，从而控制适当的发育和分化。在这里，我们通过分析 5-甲基胞嘧啶读取器 Mbd1 和修饰符 Tet1 的动态亚细胞定位以及哺乳动物细胞中 Tet 氧化产物 5-羟甲基胞嘧啶的形成，重点关注 5-甲基胞嘧啶读取器 Mbd1 和修饰符 Tet1 的相互作用。我们的结果表明 Mbd1 增强 Tet1 介导的 5-甲基胞嘧啶氧化。我们证明这是由于增强了 Tet1 在异染色质 DNA 上的定位，而不是 Tet2 和 Tet3 的定位。我们发现 Tet1 的招募及其催化活性最终导致 Mbd1 从甲基化 DNA 中被取代。最后，我们证明 Tet1 异染色质定位和 5-甲基胞嘧啶氧化的增加依赖于 Mbd1 的 CXXC3 结构域，该结构域识别未甲基化的 CpG 二核苷酸。另一方面，Mbd1 CXXC3 结构域缺失亚型仅保留与甲基化 CpG 的结合，阻断 Tet1 介导的 5-甲基胞嘧啶向 5-羟甲基胞嘧啶的转化，表明 Mbd1 亚型具有相反的生物学效应。我们的研究提供了关于胞嘧啶修饰、其修饰物和读者如何交叉调节自身的新见解。
Abstract Cytosine modifications diversify and structure the genome thereby controlling proper development and differentiation. Here, we focus on the interplay of the 5-methylcytosine reader Mbd1 and modifier Tet1 by analyzing their dynamic subcellular localization and the formation of the Tet oxidation product 5-hydroxymethylcytosine in mammalian cells. Our results demonstrate that Mbd1 enhances Tet1-mediated 5-methylcytosine oxidation. We show that this is due to enhancing the localization of Tet1, but not of Tet2 and Tet3 at heterochromatic DNA. We find that the recruitment of Tet1 and concomitantly its catalytic activity eventually leads to the displacement of Mbd1 from methylated DNA. Finally, we demonstrate that increased Tet1 heterochromatin localization and 5-methylcytosine oxidation are dependent on the CXXC3 domain of Mbd1, which recognizes unmethylated CpG dinucleotides. The Mbd1 CXXC3 domain deletion isoform, which retains only binding to methylated CpGs, on the other hand, blocks Tet1-mediated 5-methylcytosine to 5-hydroxymethylcytosine conversion, indicating opposite biological effects of Mbd1 isoforms. Our study provides new insights on how cytosine modifications, their modifiers and readers cross-regulate themselves.