Genome-wide methyl-cytosine competition by DNMT and TET
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA523851 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11215715.fastq.gz | Fastqsanger.gz | |||
| SRR11215715_1.fastq.gz | Fastqsanger.gz | |||
| SRR11215715_2.fastq.gz | Fastqsanger.gz | |||
| SRR11215716.fastq.gz | Fastqsanger.gz | |||
| SRR11215716_1.fastq.gz | Fastqsanger.gz |
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Project description: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. Examine RNA expression and DNA methylation differences between Tet-null and wild type samples of mouse epiblast in E6.5.
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Project description:Cytosine DNA bases can be methylated by DNA methyltransferases and subsequently oxidized by TET proteins. The resulting 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) are considered demethylation intermediates as well as stable epigenetic marks. To dissect the contribution of these cytosine modifying enzymes, we generated combinations of Tet knockout (KO) embryonic stem cells (ESCs) and systematically measured protein and DNA modification levels at the transition from naive to primed pluripotency. Whereas the increase of genomic 5-methylcytosine (5mC) levels during exit from pluripotency correlated with an upregulation of the de novo DNA methyltransferases DNMT3A and DNMT3B, the subsequent oxidation steps turned out to be far more complex. The strong increase of oxidized cytosine bases (5hmC, 5fC, and 5caC) was accompanied by a drop in TET2 levels, yet the analysis of KO cells suggested that TET2 is responsible for most 5fC formation. The comparison of modified cytosine and enzyme levels in Tet KO cells revealed distinct and differentiation-dependent contributions of TET1 and TET2 to 5hmC and 5fC formation arguing against a processive mechanism of 5mC oxidation. The apparent independent steps of 5hmC and 5fC formation suggest yet to be identified mechanisms regulating TET activity and may constitute another layer of epigenetic regulation.
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