Divergent DNA methylation dynamics in marsupial and eutherian embryos

Bryony J. Leeke (), Wazeer Varsally, Sugako Ogushi, Jasmin Zohren, Sergio Menchero, Aurélien Courtois, Daniel M. Snell, Aurélie Teissandier, Obah Ojarikre, Shantha K. Mahadevaiah, Fanny Decarpentrie, Rebecca J. Oakey, John L. VandeBerg and James M. A. Turner ()
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Bryony J. Leeke: The Francis Crick Institute
Wazeer Varsally: The Francis Crick Institute
Sugako Ogushi: The Francis Crick Institute
Jasmin Zohren: The Francis Crick Institute
Sergio Menchero: The Francis Crick Institute
Aurélien Courtois: The Francis Crick Institute
Daniel M. Snell: The Francis Crick Institute
Aurélie Teissandier: PSL Research University
Obah Ojarikre: The Francis Crick Institute
Shantha K. Mahadevaiah: The Francis Crick Institute
Fanny Decarpentrie: Novartis
Rebecca J. Oakey: King’s College London
John L. VandeBerg: The University of Texas Rio Grande Valley
James M. A. Turner: The Francis Crick Institute

Nature, 2025, vol. 642, issue 8069, 1073-1079

Abstract: Abstract Based on seminal work in placental species (eutherians)1–10, a paradigm of mammalian development has emerged wherein the genome-wide erasure of parental DNA methylation is required for embryogenesis. Whether such DNA methylation reprogramming is, in fact, conserved in other mammals is unknown. Here, to resolve this point, we generated base-resolution DNA methylation maps in gametes, embryos and adult tissues of a marsupial, the opossum Monodelphis domestica, revealing variations from the eutherian-derived model. The difference in DNA methylation level between oocytes and sperm is less pronounced than that in eutherians. Furthermore, unlike the genome of eutherians, that of the opossum remains hypermethylated during the cleavage stages. In the blastocyst, DNA demethylation is transient and modest in the epiblast. However, it is sustained in the trophectoderm, suggesting an evolutionarily conserved function for DNA hypomethylation in the mammalian placenta. Furthermore, unlike that in eutherians, the inactive X chromosome becomes globally DNA hypomethylated during embryogenesis. We identify gamete differentially methylated regions that exhibit distinct fates in the embryo, with some transient, and others retained and that represent candidate imprinted loci. We also reveal a possible mechanism for imprinted X inactivation, through maternal DNA methylation of the Xist-like noncoding RNA RSX11. We conclude that the evolutionarily divergent eutherians and marsupials use DNA demethylation differently during embryogenesis.

Date: 2025
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DOI: 10.1038/s41586-025-08992-2

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