Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Aug 18;60(16):2149-2162.e7.
doi: 10.1016/j.devcel.2025.03.016. Epub 2025 Apr 21.

RIF1 controls replication timing in early mouse embryos independently of lamina-associated nuclear organization

Tsunetoshi Nakatani  1 , Tamas Schauer  1 , Mrinmoy Pal  1 , Andreas Ettinger  1 , Luis Altamirano-Pacheco  1 , Julia Zorn  2 , David M Gilbert  3 , Maria-Elena Torres-Padilla  4
Affiliations

RIF1 controls replication timing in early mouse embryos independently of lamina-associated nuclear organization

Tsunetoshi Nakatani et al. Dev Cell. .

Abstract

Cells must duplicate their genome before they divide to ensure equal transmission of genetic information. The genome is replicated with a defined temporal order, replication timing (RT), which is cell-type specific and linked to 3D-genome organization. During mammalian development, RT is initially not well defined and becomes progressively consolidated from the 4-cell stage. However, the molecular regulators are unknown. Here, by combining loss-of-function analysis with genome-wide investigation of RT in mouse embryos, we identify Rap1 interacting factor 1 (RIF1) as a regulator of the progressive consolidation of RT. Embryos without RIF1 show DNA replication features of an early, more totipotent state. RIF1 regulates the progressive stratification of RT values and its depletion leads to global RT changes and a more heterogeneous RT program. Developmental RT changes are disentangled from changes in transcription and nuclear organization, specifically nuclear lamina association. Our work provides molecular understanding of replication and genome organization at the beginning of mammalian development.

Keywords: RIF1; early mouse embryos; lamina-associated domains; replication fork speed; replication timing; single-cell Repli-seq.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests M.-E.T.-P. is a member of the ethics advisory panel of MERCK.

References

    1. Aladjem MI, Rodewald LW, Lin CM, Bowman S, Cimbora DM, Brody LL, Epner EM, Groudine M, and Wahl GM (2002). Replication initiation patterns in the beta-globin loci of totipotent and differentiated murine cells: evidence for multiple initiation regions. Mol Cell Biol 22, 442–452. 10.1128/MCB.22.2.442-452.2002. - DOI - PMC - PubMed
    1. Ryba T, Hiratani I, Sasaki T, Battaglia D, Kulik M, Zhang J, Dalton S, and Gilbert DM (2011). Replication timing: a fingerprint for cell identity and pluripotency. PLoS Comput Biol 7, e1002225. 10.1371/journal.pcbi.1002225. - DOI - PMC - PubMed
    1. Alvarez V, Bandau S, Jiang H, Rios-Szwed D, Hukelmann J, Garcia-Wilson E, Wiechens N, Griesser E, Ten Have S, Owen-Hughes T, et al. (2023). Proteomic profiling reveals distinct phases to the restoration of chromatin following DNA replication. Cell Rep 42, 111996. 10.1016/j.celrep.2023.111996. - DOI - PubMed
    1. Alabert C, Bukowski-Wills JC, Lee SB, Kustatscher G, Nakamura K, de Lima Alves F, Menard P, Mejlvang J, Rappsilber J, and Groth A (2014). Nascent chromatin capture proteomics determines chromatin dynamics during DNA replication and identifies unknown fork components. Nat Cell Biol 16, 281–293. 10.1038/ncb2918. - DOI - PMC - PubMed
    1. Hiratani I, Ryba T, Itoh M, Yokochi T, Schwaiger M, Chang CW, Lyou Y, Townes TM, Schubeler D, and Gilbert DM (2008). Global reorganization of replication domains during embryonic stem cell differentiation. PLoS Biol 6, e245. 10.1371/journal.pbio.0060245. - DOI - PMC - PubMed

Substances

LinkOut - more resources