Biology subjects

Vaillant, C.

Publications and source records attributed to Vaillant, C..

5 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↗

bioRxiv2023

Decoding Nucleosome-Depleted Regions: Insights from Epigenetic Marks, Nucleosome Size, and Thermodynamic Modelling

Elucidating the global and local rules that govern genome-wide nucleosome organisation and chromatin architecture remains a critical challenge. Thermodynamic modelling based on DNA elastic properties predicts the presence of sequence-encoded nucleosome-inhibiting energy barriers (NIEBs) along vertebrate genomes. They delineate in vivo nucleosome-depleted regions (NDRs) flanked by 2-3 well positioned nucleosomes. Here, we compared mouse NIEBs to NDRs observed at CTCF binding sites and active TSSs to reveal specific chromatin organizations. We uncover in MNase-seq chromatin profiles the presence of particles of subnucleosomal length specifically positioned at the border of NIEBs with an enrichment of H3.3 and its modification H3.3 S31Ph, whereas the positioning of nucleosomes bearing H3K27ac appears insensitive to NIEBs. Surprisingly, post-translational modifications affect the size distribution of nucleosomes as seen by MNase digestion and so likely their breathing capability. We implemented an extension of our thermodynamic model allowing for variable particle size and suggest that subnucleomes at NIEB borders would result from the recruitment of chromatin remodellers at NIEBs. Our findings provide new insights into the mechanisms by which the DNA sequence and epigenetic marks shape the nucleosome positioning and breathing.

genomics↗

bioRxiv2023

Topological constraints and finite-size effects in quantitative polymer models of chromatin organization

Polymer physics simulations have provided a versatile framework to quantitatively explore the complex mechanisms driving chromosome organization. However, simulating whole chromosomes over biologically-relevant timescales at high resolution often constitutes a computationally-intensive task -- while genes or other regions of biological interest may typically only span a small fraction of the full chromosome length. Conversely, only simulating the sub-chromosomal region of interest might provide an over-simplistic or even wrong description of the mechanism controlling the 3D organization. In this work, we characterize what should be the minimal length of chromosome to be simulated in order to correctly capture the properties of a given restricted region. In particular, since the physics of long, topologically-constrained polymers may significantly deviate from those of shorter chains, we theoretically investigate how chromosomes being a long polymer quantitatively affects the structure and dynamics of its sub-segments. We show that increasing the total polymer length impacts on the topological constraints acting on the system and thus affects the compaction and mobility of sub-chains. Depending on the entanglement properties of the system, we derive a phenomenological relation defining the minimal total length to account for to maintain a correct topological regime. We finally detail the implications of these conclusions in the case of several specific biological systems. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/545312v2_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@2c8a4eorg.highwire.dtl.DTLVardef@2c1241org.highwire.dtl.DTLVardef@1628d64org.highwire.dtl.DTLVardef@130dd77_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2022

Painters in chromatin: a unified quantitative framework to systematically characterize epigenome regulation and memory

In eukaryotes, many stable and heritable phenotypes arise from the same DNA sequence, owing to epigenetic regulatory mechanisms relying on the molecular cooperativity of "reader-writer" enzymes. In this work, we focus on the fundamental, generic mechanisms behind the epigenome memory encoded by post-translational modifications of histone tails. Based on experimental knowledge, we introduce a unified modeling framework, the painter model, describing the mechanistic interplay between sequence-specific recruitment of chromatin regulators, chromatin-state-specific reader-writer processes and long-range spreading mechanisms. A systematic analysis of the model building blocks highlights the crucial impact of tridimensional chromatin organization and state-specific recruitment of enzymes on the stability of epigenomic domains and on gene expression. In particular, we show that enhanced 3D compaction of the genome and enzyme limitation facilitate the formation of ultra-stable, confined chromatin domains. The model also captures how chromatin state dynamics impact the intrinsic transcriptional properties of the region, slower kinetics leading to noisier expression. We finally apply our framework to analyze experimental data, from the propagation of{gamma} H2AX around DNA breaks in human cells to the maintenance of heterochromatin in fission yeast, illustrating how the painter model can be used to extract quantitative information on epigenomic molecular processes.

biophysics↗