Dataset Information

Active DNA demethylation during the vertebrate phylotypic period

ABSTRACT: The vertebrate body plan and organs are shaped during a highly conserved embryonic phase called the phylotypic stage, however the mechanisms that guide the epigenome through this transition and their evolutionary conservation remain elusive. Here we report widespread DNA demethylation of thousands of enhancers during the phylotypic period in zebrafish, Xenopus and mouse. These dynamic enhancers are linked to essential developmental genes that display coordinated transcriptional and epigenomic changes in the diverse vertebrates during embryogenesis. Phylotypic stage-specific binding of Tet proteins to (hydroxy)methylated DNA, and enrichment of hydroxymethylcytosine on these enhancers, implicated active DNA demethylation in this process. Furthermore, loss of function of Tet1/2/3 in zebrafish caused reduced chromatin accessibility and increased methylation levels specifically on these enhancers, indicative of DNA methylation being an upstream regulator of phylotypic enhancer function. Overall, our study reveals a novel regulatory module associated with the most conserved phase of vertebrate embryogenesis and uncovers an ancient developmental role for the Tet dioxygenases.

OTHER RELATED OMICS DATASETS IN: GSE68087PRJNA281741

INSTRUMENT(S): LTQ Orbitrap Velos, Q Exactive

ORGANISM(S): Danio Rerio (zebrafish) (brachydanio Rerio)

TISSUE(S): Whole Body

SUBMITTER: A.H. Smits

LAB HEAD: Michiel Vermeulen

PROVIDER: PXD001164 | Pride | 2016-01-27

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20121204_Velos1_MV_OB_methyl_Zebrafish_1.raw	Raw
	20121204_Velos1_MV_OB_methyl_Zebrafish_2.raw	Raw
	20121204_Velos1_MV_OB_methyl_Zebrafish_3.raw	Raw
	20121204_Velos1_MV_OB_nonmethyl_Zebrafish_1.raw	Raw
	20121204_Velos1_MV_OB_nonmethyl_Zebrafish_2.raw	Raw

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Publications

Active DNA demethylation at enhancers during the vertebrate phylotypic period.

Bogdanović Ozren O Smits Arne H AH de la Calle Mustienes Elisa E Tena Juan J JJ Ford Ethan E Williams Ruth R Senanayake Upeka U Schultz Matthew D MD Hontelez Saartje S van Kruijsbergen Ila I Rayon Teresa T Gnerlich Felix F Carell Thomas T Veenstra Gert Jan C GJ Manzanares Miguel M Sauka-Spengler Tatjana T Ecker Joseph R JR Vermeulen Michiel M Gómez-Skarmeta José Luis JL Lister Ryan R

Nature genetics 20160229 4

The vertebrate body plan and organs are shaped during a conserved embryonic phase called the phylotypic stage. However, the mechanisms that guide the epigenome through this transition and their evolutionary conservation remain elusive. Here we report widespread DNA demethylation of enhancers during the phylotypic period in zebrafish, Xenopus tropicalis and mouse. These enhancers are linked to developmental genes that display coordinated transcriptional and epigenomic changes in the diverse verte ...[more]

PMID: 26928226

Similar Datasets

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.