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Nat Genet. 2016 Apr;48(4):417-26. doi: 10.1038/ng.3522. Epub 2016 Feb 29.

Active DNA demethylation at enhancers during the vertebrate phylotypic period.

Author information

1
Australian Research Council Centre of Excellence in Plant Energy Biology, University of Western Australia, Perth, Western Australia, Australia.
2
Centro Andaluz de Biología del Desarrollo, Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Seville, Spain.
3
Harry Perkins Institute of Medical Research, Perth, Western Australia, Australia.
4
Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, the Netherlands.
5
Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
6
Genomic Analysis Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA.
7
Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, the Netherlands.
8
Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
9
Centre for Integrated Protein Science, Ludwig Maximilians Universität München, Munich, Germany.
10
Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, California, USA.

Abstract

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 vertebrates during embryogenesis. Binding of Tet proteins to (hydroxy)methylated DNA and enrichment of 5-hydroxymethylcytosine in these regions implicated active DNA demethylation in this process. Furthermore, loss of function of Tet1, Tet2 and Tet3 in zebrafish reduced chromatin accessibility and increased methylation levels specifically at these enhancers, indicative of DNA methylation being an upstream regulator of phylotypic enhancer function. Overall, our study highlights a regulatory module associated with the most conserved phase of vertebrate embryogenesis and suggests an ancient developmental role for Tet dioxygenases.

PMID:
26928226
PMCID:
PMC5912259
DOI:
10.1038/ng.3522
[Indexed for MEDLINE]
Free PMC Article

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