TET-mediated DNA demethylation controls gastrulation by regulating Lefty-Nodal signalling
TET-mediated DNA demethylation controls gastrulation by regulating Lefty-Nodal signalling
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TET 介导的 DNA 去甲基化通过调节 Lefty-Nodal 信号传导来控制原肠胚形成
DOI：
10.1038/nature20095
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发表时间：
2016-10-27
期刊：
影响因子：
64.8
通讯作者：
Xu, Guo-Liang
中科院分区：
文献类型：
--
作者：
Dai, Hai-Qiang;Wang, Bang-An;Xu, Guo-Liang
哺乳动物基因组经历表观遗传修饰，包括DNA甲基转移酶（dnmt）的胞嘧啶甲基化。10 - 11易位（TET）双加氧酶家族对5-甲基胞嘧啶的氧化可导致去甲基化（1-3）。尽管胞嘧啶甲基化在基因组印迹和x染色体失活等过程中发挥着关键作用，但胞嘧啶甲基化和去甲基化在小鼠胚胎发生中的功能意义仍有待完全确定（4-9）。本研究表明，小鼠体内所有三个Tet基因的失活导致原肠胚表型，包括与轴向中胚层成熟受损相关的原始条纹图案缺陷和旁轴向中胚层发育失败，模仿具有功能获得性节点信号的胚胎表型（10）。在Tet突变背景中引入Nodal单突变等位基因部分恢复了模式，这表明过度活跃的Nodal信号导致Tet突变体的原肠胚发育失败。Nodal信号传导增加可能是由于编码Nodal信号传导抑制剂的Lefty1和Lefty2基因表达减少所致。此外，Lefty基因表达的减少与DNA甲基化升高有关，因为当Dnmt3a和Dnmt3b基因被破坏时，在缺乏tet的胚胎中，Lefty- node信号传导和正常形态发生在很大程度上得以恢复。此外，Tet中特异性消除双加氧酶活性的点突变引起与零突变相似的形态和分子异常。综上所述，我们的研究结果表明，tet介导的5-甲基胞嘧啶氧化通过促进去甲基化来调节左节点信号，而不是DNMT3A和DNMT3B的甲基化。这些发现揭示了一个基本的表观遗传机制，其中动态DNA甲基化和去甲基化对早期身体计划形成过程中关键信号通路的调节至关重要。
Mammalian genomes undergo epigenetic modifications, including cytosine methylation by DNA methyltransferases (DNMTs). Oxidation of 5-methylcytosine by the Ten-eleven translocation (TET) family of dioxygenases can lead to demethylation(1-3). Although cytosine methylation has key roles in several processes such as genomic imprinting and X-chromosome inactivation, the functional significance of cytosine methylation and demethylation in mouse embryogenesis remains to be fully determined(4-9). Here we show that inactivation of all three Tet genes in mice leads to gastrulation phenotypes, including primitive streak patterning defects in association with impaired maturation of axial mesoderm and failed specification of paraxial mesoderm, mimicking phenotypes in embryos with gain-of-function Nodal signalling(10). Introduction of a single mutant allele of Nodal in the Tet mutant background partially restored patterning, suggesting that hyperactive Nodal signalling contributes to the gastrulation failure of Tet mutants. Increased Nodal signalling is probably due to diminished expression of the Lefty1 and Lefty2 genes, which encode inhibitors of Nodal signalling. Moreover, reduction in Lefty gene expression is linked to elevated DNA methylation, as both Lefty-Nodal signalling and normal morphogenesis are largely restored in Tet-deficient embryos when the Dnmt3a and Dnmt3b genes are disrupted. Additionally, a point mutation in Tet that specifically abolishes the dioxygenase activity causes similar morphological and molecular abnormalities as the null mutation. Taken together, our results show that TET-mediated oxidation of 5-methylcytosine modulates Lefty-Nodal signalling by promoting demethylation in opposition to methylation by DNMT3A and DNMT3B. These findings reveal a fundamental epigenetic mechanism featuring dynamic DNA methylation and demethylation crucial to regulation of key signalling pathways in early body plan formation.