Active DNA demethylation at enhancers during the vertebrate phylotypic period

Ozren Bogdanović, Arne H. Smits, Elisa De La Calle Mustienes, Juan J. Tena, Ethan Ford, Ruth Williams, Upeka Senanayake, Matthew D. Schultz, Saartje Hontelez, Ila Van Kruijsbergen, Teresa Rayon, Felix Gnerlich, Thomas Carell, Gert Jan C. Veenstra, Miguel Manzanares, Tatjana Sauka-Spengler, Joseph R. Ecker, Michiel Vermeulen, José Luis Gómez-Skarmeta, Ryan Lister

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)417-426
Number of pages10
JournalNature Genetics
Issue number4
Early online date29 Feb 2016
Publication statusPublished - Apr 2016


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