Dynamic antagonism between key repressive pathways maintains the placental 
epigenome

Weigert, Raha; Hetzel, Sara; Bailly, Nina; Haggerty, Chuck; Ilik, Ibrahim A.; Kwong Yung, Philip Yuk; Navarro, Carmen; Bolondi, Adriano; Sampath Kumar, Abhishek; Anania, Chiara; Brändl, Björn; Meierhofer, David; Lupiáñez, Darío G.; Müller, Franz-Josef; Aktas, Tugce; Elsässer, Simon J.; Kretzmer, Helene; Smith, Zachary D.; Meissner, Alexander

doi:10.1038/s41556-023-01114-y

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Dynamic antagonism between key repressive pathways maintains the placental epigenome

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Weigert, Raha
Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Hetzel, Sara
Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Bailly, Nina
Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Haggerty, Chuck
Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Ilik, Ibrahim A.
Quantitative RNA Biology (Tugce Aktas), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Bolondi, Adriano
Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Sampath Kumar, Abhishek
Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Brändl, Björn
Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Meierhofer, David
Mass Spectrometry Facility (Head: David Meierhofer), Scientific Service (Head: Claudia Thurow), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Müller, Franz-Josef
Cellular Phenotyping (Franz-Josef Müller), Dept. of Genome Regulation, (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

/persons/resource/persons231875

Aktas, Tugce
Quantitative RNA Biology (Tugce Aktas), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Kretzmer, Helene
Computational Genomics (Helene Kretzmer), Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Smith, Zachary D.
Smith Lab/Developmental Genome Biology, Max Planck Institute for Molecular Genetics, Max Planck Society;

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Meissner, Alexander
Meissner Lab/Genome Regulation, Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;

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NatCellBiol_Weigert et al_2023.pdf
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Citation

Weigert, R., Hetzel, S., Bailly, N., Haggerty, C., Ilik, I. A., Kwong Yung, P. Y., et al. (2023). Dynamic antagonism between key repressive pathways maintains the placental epigenome. Nature Cell Biology, 25(4), 579-591. doi:10.1038/s41556-023-01114-y.

Cite as: https://hdl.handle.net/21.11116/0000-000D-1F8D-3

Abstract

DNA and Histone 3 Lysine 27 methylation typically function as repressive modifications and operate within distinct genomic compartments. In mammals, the majority of the genome is kept in a DNA methylated state, whereas the Polycomb repressive complexes regulate the unmethylated CpG-rich promoters of developmental genes. In contrast to this general framework, the extra-embryonic lineages display non-canonical, globally intermediate DNA methylation levels, including disruption of local Polycomb domains. Here, to better understand this unusual landscape's molecular properties, we genetically and chemically perturbed major epigenetic pathways in mouse trophoblast stem cells. We find that the extra-embryonic epigenome reflects ongoing and dynamic de novo methyltransferase recruitment, which is continuously antagonized by Polycomb to maintain intermediate, locally disordered methylation. Despite its disorganized molecular appearance, our data point to a highly controlled equilibrium between counteracting repressors within extra-embryonic cells, one that can seemingly persist indefinitely without bistable features typically seen for embryonic forms of epigenetic regulation.