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

doi:10.1038/ng.3522

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

^*Corresponding author for this work

Division of Developmental Biology & Medicine (L5)

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	417-426
Number of pages	10
Journal	Nature Genetics
Volume	48
Issue number	4
Early online date	29 Feb 2016
DOIs	https://doi.org/10.1038/ng.3522
Publication status	Published - Apr 2016

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Bogdanović, O., Smits, A. H., De La Calle Mustienes, E., Tena, J. J., Ford, E., Williams, R., Senanayake, U., Schultz, M. D., Hontelez, S., Van Kruijsbergen, I., Rayon, T., Gnerlich, F., Carell, T., Veenstra, G. J. C., Manzanares, M., Sauka-Spengler, T., Ecker, J. R., Vermeulen, M., Gómez-Skarmeta, J. L., & Lister, R. (2016). Active DNA demethylation at enhancers during the vertebrate phylotypic period. Nature Genetics, 48(4), 417-426. https://doi.org/10.1038/ng.3522

@article{0043bcee509e4741ab7f8eda80a87de1,

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.",

author = "Ozren Bogdanovi{\'c} and Smits, {Arne H.} and {De La Calle Mustienes}, Elisa and Tena, {Juan J.} and Ethan Ford and Ruth Williams and Upeka Senanayake and Schultz, {Matthew D.} and Saartje Hontelez and {Van Kruijsbergen}, Ila and Teresa Rayon and Felix Gnerlich and Thomas Carell and Veenstra, {Gert Jan C.} and Miguel Manzanares and Tatjana Sauka-Spengler and Ecker, {Joseph R.} and Michiel Vermeulen and G{\'o}mez-Skarmeta, {Jos{\'e} Luis} and Ryan Lister",

note = "Publisher Copyright: {\textcopyright} 2016 Nature America, Inc.",

year = "2016",

month = apr,

doi = "10.1038/ng.3522",

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volume = "48",

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Bogdanović, O, Smits, AH, De La Calle Mustienes, E, Tena, JJ, Ford, E, Williams, R, Senanayake, U, Schultz, MD, Hontelez, S, Van Kruijsbergen, I, Rayon, T, Gnerlich, F, Carell, T, Veenstra, GJC, Manzanares, M, Sauka-Spengler, T, Ecker, JR, Vermeulen, M, Gómez-Skarmeta, JL & Lister, R 2016, 'Active DNA demethylation at enhancers during the vertebrate phylotypic period', Nature Genetics, vol. 48, no. 4, pp. 417-426. https://doi.org/10.1038/ng.3522

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AU - Ford, Ethan

AU - Williams, Ruth

AU - Senanayake, Upeka

AU - Schultz, Matthew D.

AU - Hontelez, Saartje

AU - Van Kruijsbergen, Ila

AU - Rayon, Teresa

AU - Gnerlich, Felix

AU - Carell, Thomas

AU - Veenstra, Gert Jan C.

AU - Manzanares, Miguel

AU - Sauka-Spengler, Tatjana

AU - Ecker, Joseph R.

AU - Vermeulen, Michiel

AU - Gómez-Skarmeta, José Luis

AU - Lister, Ryan

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AB - 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.

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JO - Nature Genetics

JF - Nature Genetics

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Active DNA demethylation at enhancers during the vertebrate phylotypic period

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