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| Status |
Public on Oct 27, 2016 |
| Title |
DNA demethylation by Tet dioxygenases controls gastrula patterning by regulating Lefty-Nodal signaling |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Methylation profiling by high throughput sequencing
|
| Summary |
Mammalian genomes are subjected to epigenetic modifications, including cytosine methylation by DNA methyltransferases (Dnmt) and further oxidation by Ten-eleven-translocation (Tet) family of dioxygenases. Cytosine methylation plays key roles in multiple processes such as genomic imprinting and X-chromosome inactivation. However, the functional significance of cytosine methylation and the further oxidation has remained undetermined in mouse embryogenesis. Here we show that global inactivation of all three Tet genes in mice led to consistent defects in gastrulation. The defects include reduced specification of the axial mesoderm and paraxial mesoderm, mimicking phenotypes in embryos with gain-of-function Nodal signaling, a cardinal cue for gastrulation. Introduction of a single mutant allele of Nodal in the Tet mutant background partially restored patterning, suggesting that hyperactive Nodal signaling is a leading cause for the gastrulation failure of Tet mutants. Increased Nodal signaling is likely due to diminished expression of the Lefty1 and Lefty2 genes, inhibitors of Nodal signaling. Moreover, reduction in the Lefty gene expression can be ascribed to elevated DNA methylation as both Lefty-Nodal signaling and normal morphogenesis are largely restored in Tet-deficient embryos when the Dnmt3a and Dnmt3b genes are disrupted. Additionally, specific inactivation of Tet by point mutations abolishing the dioxygenase activity causes similar molecular and gastrulation abnormalities. Taken together, our results show that Tet-mediated DNA oxidation modulates the Lefty-Nodal signaling by promoting demethylation of the shared target genes with Dnmt3a and Dnmt3b. These findings reveal a fundamental epigenetic mechanism featuring dynamic DNA methylation and demethylation and their role in the regulation of key signaling in body plan formation during early embryogenesis.
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| Overall design |
Examine RNA expression and DNA methylation differences between Tet-null and wild type samples of mouse epiblast in E6.5.
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| Citation(s) |
27760115 |
| Submission date |
Dec 22, 2015 |
| Last update date |
Jul 06, 2022 |
| Contact name |
Rui WANG |
| E-mail(s) |
fish_cat_wr@sina.cn
|
| Phone |
15801166445
|
| Organization name |
Peking University
|
| Department |
Biodynamics Optical Imaging Center (BIOPIC)
|
| Lab |
Fuchou Tang
|
| Street address |
No.5 Yiheyuan Road, Haidian District
|
| City |
Beijing |
| ZIP/Postal code |
100871 |
| Country |
China |
| |
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| Platforms (2) |
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| Samples (20)
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| Relations |
| Reanalyzed by |
GSE171332 |
| BioProject |
PRJNA306858 |
| SRA |
SRP067746 |
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