title: Active DNA demethylation at enhancers during the vertebrate phylotypic period.
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.
authors.affiliation: Australian Research Council Centre of Excellence in Plant Energy Biology, University of Western Australia, Perth, Western Australia, Australia.|Centro Andaluz de Biología del Desarrollo, Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Seville, Spain.|Harry Perkins Institute of Medical Research, Perth, Western Australia, Australia.
authors.forename: Ozren
authors.initials: O
authors.lastname: Bogdanović
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, the Netherlands.
authors.forename: Arne H
authors.initials: AH
authors.lastname: Smits
authors.affiliation: Centro Andaluz de Biología del Desarrollo, Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Seville, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: de la Calle Mustienes
authors.affiliation: Centro Andaluz de Biología del Desarrollo, Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Seville, Spain.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Tena
authors.affiliation: Australian Research Council Centre of Excellence in Plant Energy Biology, University of Western Australia, Perth, Western Australia, Australia.|Harry Perkins Institute of Medical Research, Perth, Western Australia, Australia.
authors.forename: Ethan
authors.initials: E
authors.lastname: Ford
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Williams
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Upeka
authors.initials: U
authors.lastname: Senanayake
authors.affiliation: Genomic Analysis Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Schultz
authors.affiliation: Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, the Netherlands.
authors.forename: Saartje
authors.identifier: http://orcid.org/0000-0002-5286-7859
authors.initials: S
authors.lastname: Hontelez
authors.affiliation: Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, the Netherlands.
authors.forename: Ila
authors.initials: I
authors.lastname: van Kruijsbergen
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Rayon
authors.affiliation: Centre for Integrated Protein Science, Ludwig Maximilians Universität München, Munich, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Gnerlich
authors.affiliation: Centre for Integrated Protein Science, Ludwig Maximilians Universität München, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Carell
authors.affiliation: Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, the Netherlands.
authors.forename: Gert Jan C
authors.identifier: http://orcid.org/0000-0002-7787-4940
authors.initials: GJ
authors.lastname: Veenstra
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Manzanares
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Sauka-Spengler
authors.affiliation: Genomic Analysis Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA.|Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Ecker
authors.affiliation: Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, the Netherlands.
authors.forename: Michiel
authors.initials: M
authors.lastname: Vermeulen
authors.affiliation: Centro Andaluz de Biología del Desarrollo, Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Seville, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Gómez-Skarmeta
authors.affiliation: Australian Research Council Centre of Excellence in Plant Energy Biology, University of Western Australia, Perth, Western Australia, Australia.|Harry Perkins Institute of Medical Research, Perth, Western Australia, Australia.
authors.forename: Ryan
authors.identifier: http://orcid.org/0000-0001-6637-7239
authors.initials: R
authors.lastname: Lister
mesh_terms: D000818:Animals; D019521:Body Patterning; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D014981:Xenopus; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D029961:Zebrafish Proteins