Emergence of replication timing during early mammalian development

Tsunetoshi Nakatani, Tamas Schauer, Luis Altamirano-Pacheco, Kyle N. Klein, Andreas Ettinger, Mrinmoy Pal, David M. Gilbert and Maria-Elena Torres-Padilla ()
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Tsunetoshi Nakatani: Helmholtz Munich
Tamas Schauer: Helmholtz Munich
Luis Altamirano-Pacheco: Helmholtz Munich
Kyle N. Klein: Florida State University
Andreas Ettinger: Helmholtz Munich
Mrinmoy Pal: Helmholtz Munich
David M. Gilbert: San Diego Biomedical Research Institute
Maria-Elena Torres-Padilla: Helmholtz Munich

Nature, 2024, vol. 625, issue 7994, 401-409

Abstract: Abstract DNA replication enables genetic inheritance across the kingdoms of life. Replication occurs with a defined temporal order known as the replication timing (RT) programme, leading to organization of the genome into early- or late-replicating regions. RT is cell-type specific, is tightly linked to the three-dimensional nuclear organization of the genome1,2 and is considered an epigenetic fingerprint3. In spite of its importance in maintaining the epigenome4, the developmental regulation of RT in mammals in vivo has not been explored. Here, using single-cell Repli-seq5, we generated genome-wide RT maps of mouse embryos from the zygote to the blastocyst stage. Our data show that RT is initially not well defined but becomes defined progressively from the 4-cell stage, coinciding with strengthening of the A and B compartments. We show that transcription contributes to the precision of the RT programme and that the difference in RT between the A and B compartments depends on RNA polymerase II at zygotic genome activation. Our data indicate that the establishment of nuclear organization precedes the acquisition of defined RT features and primes the partitioning of the genome into early- and late-replicating domains. Our work sheds light on the establishment of the epigenome at the beginning of mammalian development and reveals the organizing principles of genome organization.

Date: 2024
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DOI: 10.1038/s41586-023-06872-1

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