Dynamic antagonism between key repressive pathways maintains the placental epigenome (source data and custom code)
Creators
- Weigert, Raha1
- Hetzel, Sara1
- Bailly, Nina1
- Haggerty, Chuck1
- Ilik, Ibrahim A.2
- Kwong Yung, Philip Y.3
- Navarro, Carmen3
- Bolondi, Adriano1
- Sampath Kumar, Abhishek1
- Anania, Chiara4
- Brändl, Björn5
- Meierhofer, David6
- Lupiáñez, Darío G.4
- Müller, Franz-Josef5
- Aktas, Tugce2
- Elsässer, Simon J.3
- Kretzmer, Helene1
- Smith, Zachary D.7
- Meissner, Alexander1
- 1. Department of Genome Regulation, Max Planck Institute for Molecular Genetics
- 2. Otto Warburg Laboratories, Max Planck Institute for Molecular Genetics
- 3. Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet
- 4. Epigenetics and Sex Development Group, Berlin Institute for Medical Systems Biology, Max-Delbrück Center for Molecular Medicine
- 5. Universitätsklinikum Schleswig-Holstein Campus Kiel, Zentrum für Integrative Psychiatrie gGmbH
- 6. Mass Spectrometry Joint Facilities Scientific Service, Max Planck Institute for Molecular Genetics
- 7. Department of Genetics, Yale Stem Cell Center, Yale School of Medicine
Description
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 CpG-rich promoters of developmental genes. In contrast to this general framework, the extraembryonic lineages display noncanonical, globally intermediate DNA methylation levels that includes disruption of local Polycomb domains. To better understand this unusual landscape’s molecular properties, we genetically and chemically perturbed major epigenetic pathways in mouse Trophoblast Stem Cells (TSCs). We find that the extraembryonic epigenome reflects ongoing and dynamic de novo methyltransferase recruitment, which is continuously antagonized by Polycomb to maintain intermediate, locally disordered methylation. Despite its disorganized appearance, our data point to a highly controlled equilibrium between counteracting repressors within extraembryonic cells, one that can seemingly persist indefinitely without bistable features typically seen for embryonic forms of epigenetic regulation.
Files
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