Biology subjects

D'Asaro, D.

Publications and source records attributed to D'Asaro, D..

2 recordsLinked to original sources

bioRxiv2025

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

Although significant progress has been made on our understanding of DNA replication and spatial chromosome organization in eukaryotes, how they both 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. 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 produce 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. Overall, our model offers new insights into the spatial and dynamic organization of chromatin during replication in eukaryotes.

biophysics↗

bioRxiv2024

DNA replication and polymer chain duplication reshape the genome in space and time

In eukaryotes, DNA replication constitutes a complex process whereby multiple origins are stochastically fired, and from which the replication machinery proceeds along chromosomes to achieve the faithful synthesis of two identical copies of the genome during the S-phase of the cell cycle. Experimental evidence show a functional correlation between the dynamics of replication and the spatial organization of the genome inside cell nuclei, suggesting that the process of replicating DNA may impact chromosome folding. However, the theoretical and mechanistic bases of such an hypothesis remain elusive. To address that question, we propose a quantitative, minimal framework that integrates the dynamics of replication along a polymer chain by accounting explicitly for the progression of the replication machinery and the resulting formation of sister chromatids. By systematically characterizing the 3D structural consequences of replication, and of possible interactions between active replication machineries, we show that the formation of transient loops may potentially impact chromosome organization across multiple temporal and spatial scales, from the level of individual origins to that of the global polymer chain. Comparison with available microscopy and chromosome conformation capture data in yeast suggests that a replication-dependent loop extrusion process may be acting in vivo, and may shape chromosomes as loose polymer bottle-brushes during the S-phase. Lastly, we explore the post-replication relative organization of sister chromatids and demonstrate the emergence of catenations and intertwined structures, which are regulated by the density of fired origins.

biophysics↗