Journal Article

TET-mediated DNA demethylation controls gastrulation by regulating Lefty–Nodal signalling

Tang, Fuchou, Chapman, Deborah L., Wang, Bang-An, Yang, Lu, Sun, Xin, Xu, Guo-Liang, Zhu, Guo-Chun, Sun, Mei-Ling, Chen, Jia-Jia, Ge, Hao, Dai, Hai-Qiang, Wang, Rui

2016

Overview

Inactivation of three Tet genes in mice leads to gastrulation phenotypes similar to those in embryos with increased Nodal signalling, revealing a functional redundancy of Tet genes and showing balanced and dynamic DNA methylation and demethylation is crucial to regulate key signalling pathways in early body plan formation. Dnmt and Tet enzymes controls Nodal signalling The importance of DNA methylation and its removal by the TET family enzymes during embryo development have been a much debated area of research. Here, Guo-Liang Xu and colleagues show that inactivation of all three Tet genes in mice leads to gastrulation phenotypes similar to those in embryos with increased Nodal signalling. Expression of inhibitors of Nodal signalling is diminished and can be restored when the Dnmt3a/b genes are inactivated. These alterations do not occur if one of the Tet genes remains intact. These findings reveal a functional redundancy of Tet genes and show that balanced and dynamic DNA methylation and demethylation is crucial in regulation of key signalling pathways in early body plan formation 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 , 2 , 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 , 5 , 6 , 7 , 8 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 5-Methylcytosine - metabolism / 631/136/2086/2127 / 631/337/176/1988 / Animals / Cell growth / Deoxyribonucleic acid / Dioxygenases - deficiency / Dioxygenases - genetics / Dioxygenases - metabolism / DNA / DNA (Cytosine-5-)-Methyltransferases - metabolism / DNA methylation / DNA Methylation - genetics / DNA Methyltransferase 3A / DNA Methyltransferase 3B / DNA-Binding Proteins - deficiency / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Embryo, Mammalian - embryology / Embryo, Mammalian - enzymology / Embryo, Mammalian - metabolism / Embryonic growth stage / Embryos / Enhancer Elements, Genetic - genetics / Enzymes / Epigenesis, Genetic / Female / Gastrulation - genetics / Gene expression / Humanities and Social Sciences / Inactivation / Left-Right Determination Factors - metabolism / letter / Male / Mesoderm - embryology / Mesoderm - metabolism / Mice / Morphogenesis / Morphology / multidisciplinary / Mutation / Nodal Protein - metabolism / Oxidation / Oxidation-Reduction / Promoter Regions, Genetic - genetics / Proto-Oncogene Proteins - deficiency / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins - metabolism / Science / Signal transduction / Signal Transduction - genetics / Translocation