Biology subjects

Delamarre, A.

Publications and source records attributed to Delamarre, A..

5 recordsLinked to original sources

bioRxiv2026

Understanding the role of chromatin accessibility and compaction on loop extrusion dynamics

Loop extrusion by SMC complexes is a fundamental mechanism regulating the three-dimensional genome organization, but how these molecular motors navigate through the crowded, nucleosome-covered chromatin fiber remains an open question. Here, we develop a stochastic biophysical model of loop extrusion that explicitly couples motor stepping dynamics to chromatin accessibility and compaction. First, we systematically analyze the role of accessibility on its dynamics across homogeneous, periodic, and random roadblock positioning along chromatin. This comprehensive analysis reveals distinct dynamic regimes: phase-dependent kinetics in periodic arrays where motor step size aligns with obstacle spacing, and anomalous sub-linear progression in disordered environments due to rare but long-lived trapping events. Then, we contextualize our framework to nucleosome-like arrays. Our simulations reveal a non-intuitive dual role for nucleosomes: while they hinder extruder progression by blocking access to linker DNA, their high compaction packs more base pairs per physical distance, enabling larger genomic displacements per step. Strikingly, the resulting base-pair extrusion speed displays a non-monotonic dependence on nucleosome spacing, reaching a maximum at intermediate linker lengths (10-70 bp) that can exceed the speed on naked DNA. Finally, in support of this mechanism, analysis of yeast genomic data shows that a higher nucleosome occupancy between cohesin-associated regions correlates with stronger contact enrichment, consistent with compaction-enhanced extrusion efficiency in vivo. These findings establish chromatin architecture as a tunable regulator of loop extrusion, explaining the comparable speeds observed in vitro and in vivo and providing a quantitative framework for understanding how genome organization emerges from the interplay between motor kinetics and chromatin structure.

biophysics↗

bioRxiv2025

CAD-C reveals centromere pairing and near-perfect alignment of sister chromatids

Three-dimensional (3D) genome organization plays a central role in gene regulation, chromatin folding, and genome stability. Although chromosome-conformation capture (3C)-derived methods have revolutionized our understanding of genome architecture, most remain limited in resolution, in their capacity to detect multiway interactions and in their ability to distinguish sister chromatids. Here, we present CAD-C, a new chromatin-conformation capture strategy that uses Caspase-Activated DNase (CAD) to fragment chromatin. Fragmentation of chromatin to the nucleosome level by CAD digestion substantially enhances proximity ligation, enabling formation of multi-nucleosome ligation products. Nanopore sequencing of these long DNA molecules allows reconstruction of chromatin fiber connectivity and 3D contact maps with single nucleosome resolution. Importantly, CAD-C is able to identify sister-chromatid interactions at high resolution which reveals that centromeres are closely paired and that cohesin maintains sister chromatids in near perfect alignment where the same nucleosomes are associated across sisters. Such precise alignment has significant implications for chromosome structure and the mechanisms by which cohesion is established.

genomics↗

bioRxiv2025

Condensin and topoisomerases cooperate to relieve topological stress at stalled replication forks

Resolving complex topological structures at replication forks is vital for successful DNA replication, but the mechanisms are little understood. Evidence from diverse eukaryotes suggests that condensin - which promotes chromosome condensation in M phase - might also act during S phase to facilitate relaxation of torsional stress by topoisomerases. Here, we show in yeast and human cells that condensin binds stressed replication forks, where it cooperates with topoisomerases I and II to promote resection of the nascent DNA and restart replication. Our findings suggest that condensin acts with topoisomerase I at reversed forks to convert positively supercoiled DNA into structures that are subsequently relaxed by topoisomerase 2, allowing the fork to resume replication. These findings uncover an important, evolutionarily conserved role for condensin in handling topological constraints at arrested forks that is reminiscent of its function in chromosome segregation and might prevent formation of toxic chromosome structures during fork arrest and reversal.

genetics↗

bioRxiv2025

Proteomic profiling of advanced hepatocellular carcinoma identifies predictive signatures of response to treatments

PurposeHepatocellular carcinoma (HCC) is the most common form of liver cancer with a bad prognosis in case of advanced HCC, only eligible for palliative systemic therapies. After a decade of exclusive sorafenib monotherapy, with a response rate of <10%, the advent of immunotherapies represents a revolution in HCC. The combination of atezolizumab/bevacizumab is recommended as the first-line systemic treatment, with a response rate around 30%. However, there are currently no predictive factors for response to these treatment options. Experimental DesignWe profiled, by high-resolution mass spectrometry-based proteomics combined with machine learning analysis, a selected cohort of fixed biopsies of advanced HCC. We grouped subjects according to their objective response to treatments, corresponded to a tumor regression vs tumor progression at 4 months after treatment. ResultsWe generated a proteome database of 50 selected HCC samples. We compared the relative protein abundance between tumoral and non-tumoral liver tissues from advanced HCC patients treated. The clear distinction of these two groups for each treatment is based on deregulation for 141 protein or 87 for atezolizumab/bevacizumab and sorafenib treatment, respectively. These specific proteomic signatures were sufficient to predict the response to treatment, and revealed biological pathways involved in treatments resistance. Particularly, we validated a shift in tumor cell metabolism with an immunosuppressive environment involved in the resistance to atezolizumab/bevacizumab combination. ConclusionsWe performed an in-depth analysis of quantitative proteomic data from HCC biopsies to predict the treatment response to advanced HCC giving the ability to optimize patient management.

cancer biology↗

bioRxiv2024

Chromatin architecture mapping by multiplex proximity tagging

Chromatin plays a pivotal role in genome expression, maintenance, and replication. To better understand chromatin organization, we developed a novel proximity-tagging method which assigns unique DNA barcodes to molecules that associate in 3D space. Using this method - Proximity Copy Paste (PCP) - we mapped the connectivity of individual nucleosomes in Saccharomyces cerevisiae. By analyzing nucleosome positions and spacing on single molecule fibers, we show that chromatin is predominantly organized into regularly spaced nucleosome arrays that can be positioned or delocalized. Basic features of nucleosome arrays are generally explained by gene size and transcription. PCP can also map long-range, multi-way interactions and we provide the first direct evidence supporting a model that metaphase chromosomes are compacted by cohesin loop clustering. Analyzing single-molecule nuclease footprinting data we define distinct chromatin states within a mixed population to show that non-canonical nucleosomes, notably Overlapping-Di-Nucleosomes (OLDN) are a stable feature of chromatin. PCP is a versatile method allowing the detection of the connectivity of individual molecules locally and over large distance to be mapped at high-resolution in a single experiment.

molecular biology↗