Recent evolution of a TET-controlled and DPPA3/STELLA-driven pathway of passive DNA demethylation in mammals

Christopher B. Mulholland, Atsuya Nishiyama, Joel Ryan, Ryohei Nakamura, Merve Yiğit, Ivo M. Glück, Carina Trummer, Weihua Qin, Michael D. Bartoschek, Franziska R. Traube, Edris Parsa, Enes Ugur, Miha Modic, Aishwarya Acharya, Paul Stolz, Christoph Ziegenhain, Michael Wierer, Wolfgang Enard, Thomas Carell, Don C. Lamb, Hiroyuki Takeda, Makoto Nakanishi, Sebastian Bultmann () and Heinrich Leonhardt ()
Additional contact information
Christopher B. Mulholland: Ludwig-Maximilians-Universität München
Atsuya Nishiyama: The University of Tokyo
Joel Ryan: Ludwig-Maximilians-Universität München
Ryohei Nakamura: The University of Tokyo
Merve Yiğit: Ludwig-Maximilians-Universität München
Ivo M. Glück: Ludwig-Maximilians-Universität München
Carina Trummer: Ludwig-Maximilians-Universität München
Weihua Qin: Ludwig-Maximilians-Universität München
Michael D. Bartoschek: Ludwig-Maximilians-Universität München
Franziska R. Traube: Ludwig-Maximilians-Universität München
Edris Parsa: Ludwig-Maximilians-Universität München
Enes Ugur: Ludwig-Maximilians-Universität München
Miha Modic: The Francis Crick Institute and UCL Queen Square Institute of Neurology
Aishwarya Acharya: Ludwig-Maximilians-Universität München
Paul Stolz: Ludwig-Maximilians-Universität München
Christoph Ziegenhain: Ludwig-Maximilians-Universität München
Michael Wierer: Max Planck Institute for Biochemistry
Wolfgang Enard: Ludwig-Maximilians-Universität München
Thomas Carell: Ludwig-Maximilians-Universität München
Don C. Lamb: Ludwig-Maximilians-Universität München
Hiroyuki Takeda: The University of Tokyo
Makoto Nakanishi: The University of Tokyo
Sebastian Bultmann: Ludwig-Maximilians-Universität München
Heinrich Leonhardt: Ludwig-Maximilians-Universität München

Nature Communications, 2020, vol. 11, issue 1, 1-24

Abstract: Abstract Genome-wide DNA demethylation is a unique feature of mammalian development and naïve pluripotent stem cells. Here, we describe a recently evolved pathway in which global hypomethylation is achieved by the coupling of active and passive demethylation. TET activity is required, albeit indirectly, for global demethylation, which mostly occurs at sites devoid of TET binding. Instead, TET-mediated active demethylation is locus-specific and necessary for activating a subset of genes, including the naïve pluripotency and germline marker Dppa3 (Stella, Pgc7). DPPA3 in turn drives large-scale passive demethylation by directly binding and displacing UHRF1 from chromatin, thereby inhibiting maintenance DNA methylation. Although unique to mammals, we show that DPPA3 alone is capable of inducing global DNA demethylation in non-mammalian species (Xenopus and medaka) despite their evolutionary divergence from mammals more than 300 million years ago. Our findings suggest that the evolution of Dppa3 facilitated the emergence of global DNA demethylation in mammals.

Date: 2020
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DOI: 10.1038/s41467-020-19603-1

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