Sex-specific DNA-replication in the early mammalian embryo

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The timing of DNA replication in mammals is crucial for minimizing errors and influenced by genome usage and chromatin states. Replication timing in the newly formed mammalian embryo remains poorly understood. Here, we have investigated replication timing in mouse zygotes and 2-cell embryos, revealing that zygotes lack a conventional replication timing program, which then emerges in 2-cell embryos. This program differs from embryonic stem cells and generally correlates with transcription and genome compartmentalization of both parental genomes. However, consistent and systematic differences existed between the replication timing of the two parental genomes, including considerably later replication of maternal pericentromeric regions compared to paternal counterparts. Moreover, maternal chromatin modified by Polycomb Repressive Complexes in the oocyte, undergoes early replication, despite belonging to the typically late-replicating B-compartment of the genome. This atypical and asynchronous replication of the two parental genomes may advance our understanding of replication stress in early human embryos and trigger strategies to reduce errors and aneuploidies.
OriginalsprogEngelsk
Artikelnummer6323
TidsskriftNature Communications
Vol/bind15
Udgave nummer1
Antal sider15
ISSN2041-1723
DOI
StatusUdgivet - 2024

Bibliografisk note

Funding Information:
We thank the members of the Hoffmann lab and Center for Chromosome Stability, as well as Mika Zagrobelny Larsen, for support and critical suggestions throughout this work. We thank Ricardo Alonso Laguna Barraza, Rodrigo Dos A Garcia, and Ioana Maria Zah of the Core Facility of Transgenic Mice, The University of Copenhagen, for their technical support. We acknowledge the Core Facility for Integrated Microscopy, Faculty of Health and Medical Sciences, University of Copenhagen. We would like to express our gratitude to David Gilbert and Vishnu Dileep for their valuable guidance on single-cell Repli-Seq methodology. Additionally, we appreciate the insightful discussions and assistance provided by Ichiro Hiratani and Hisashi Miura during the initial phase of establishing the single-cell Repli-Seq methodology. We express our gratitude to Zhenhai Du, Mate Borsos, and Wei Xie for generously sharing the PC1 scores derived from previously published HiC data of mouse embryos. This work was supported by the Danish National Research Foundation DNRF115 (J.A.H, E.R.H., and M.L), the Lundbeck Foundation, R347-2020-2177 (J.A.H.), the Novo Nordisk Foundation, NNF22OC0080710 (M.L.), NNF22OC0074308 (E.R.H.), NNF15COC0016662 (E.R.H.), the Norwegian Research Council\u2019s Center of Excellence Program (M.L. and J.A.D.), the ERC, 724718-ReCAP (E.R.H.), and the Independent Research Council Denmark, DFF-FSS 0134-00299B (E.R.H.).

Publisher Copyright:
© The Author(s) 2024.

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