Genome-wide modeling of DNA replication in space and time confirms the emergence of replication specific patterns in vivo in eukaryotes.

BACKGROUND: Although significant progress has been made in our understanding of DNA replication and spatial chromosome organization in eukaryotes, how they interplay remains elusive. In particular, from the local structure of two diverging sister-forks to the higher-level organization of the replication machinery into nuclear domains, the mechanistic details of chromatin duplication in the 3D nuclear space remain debated. RESULTS: In this study, we use a computational model of the Saccharomyces cerevisiae genome to explore how replication influences chromatin folding. By integrating both a realistic description of the genome 3D architecture and 1D replication timing, simulations reveal that the colocalization of sister-forks produces a characteristic “fountain” pattern around early origins of replication. We confirm the presence of similar features in vivo in early S-phase with new Hi-C data in various conditions, showing that it is replication-dependent and cohesin-independent. At a larger scale, we show that the 3D genome leads to forks being highly enriched at one pole of the nucleus in early S-phase, before later redistributing more homogeneously, and may favor the higher-order clustering of forks into Replication Foci, as observed in earlier microscopy experiments. Additionally, replication causes temporary chromatin slowdown and reduced mobility due to fork passage and sister chromatid intertwining. CONCLUSIONS: Overall, our model offers new insights into the spatial and dynamic organization of chromatin during replication in eukaryotes. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-025-03872-4.