Rouse model with transient intramolecular contacts on a timescale of seconds recapitulates folding and fluctuation of yeast chromosomes.

DNA folding and dynamics along with major nuclear functions are determined by chromosome structural properties, which remain, thus far, elusive in vivo. Here, we combine polymer modeling and single particle tracking experiments to determine the physico-chemical parameters of chromatin in vitro and in living yeast. We find that the motion of reconstituted chromatin fibers can be recapitulated by the Rouse model using mechanical parameters of nucleosome arrays deduced from structural simulations. Conversely, we report that the Rouse model shows some inconsistencies to analyze the motion and structural properties inferred from yeast chromosomes determined with chromosome conformation capture techniques (specifically, Hi-C). We hence introduce the Rouse model with Transient Internal Contacts (RouseTIC), in which random association and dissociation occurs along the chromosome contour. The parametrization of this model by fitting motion and Hi-C data allows us to measure the kinetic parameters of the contact formation reaction. Chromosome contacts appear to be transient; associated to a lifetime of seconds and characterized by an attractive energy of -0.3 to -0.5 kBT. We suggest attributing this energy to the occurrence of histone tail-DNA contacts and notice that its amplitude sets chromosomes in 'theta' conditions, in which they are poised for compartmentalization and phase separation.

Network Modeling of Crohn's Disease Incidence.

BACKGROUND: Numerous genetic and environmental risk factors play a role in human complex genetic disorders (CGD). However, their complex interplay remains to be modelled and explained in terms of disease mechanisms. METHODS AND FINDINGS: Crohn's Disease (CD) was modeled as a modular network of patho-physiological functions, each summarizing multiple gene-gene and gene-environment interactions. The disease resulted from one or few specific combinations of module functional states. Network aging dynamics was able to reproduce age-specific CD incidence curves as well as their variations over the past century in Western countries. Within the model, we translated the odds ratios (OR) associated to at-risk alleles in terms of disease propensities of the functional modules. Finally, the model was successfully applied to other CGD including ulcerative colitis, ankylosing spondylitis, multiple sclerosis and schizophrenia. CONCLUSION: Modeling disease incidence may help to understand disease causative chains, to delineate the potential of personalized medicine, and to monitor epidemiological changes in CGD.

Modeling epigenome folding: formation and dynamics of topologically associated chromatin domains.

Genomes of eukaryotes are partitioned into domains of functionally distinct chromatin states. These domains are stably inherited across many cell generations and can be remodeled in response to developmental and external cues, hence contributing to the robustness and plasticity of expression patterns and cell phenotypes. Remarkably, recent studies indicate that these 1D epigenomic domains tend to fold into 3D topologically associated domains forming specialized nuclear chromatin compartments. However, the general mechanisms behind such compartmentalization including the contribution of epigenetic regulation remain unclear. Here, we address the question of the coupling between chromatin folding and epigenome. Using polymer physics, we analyze the properties of a block copolymer model that accounts for local epigenomic information. Considering copolymers build from the epigenomic landscape of Drosophila, we observe a very good agreement with the folding patterns observed in chromosome conformation capture experiments. Moreover, this model provides a physical basis for the existence of multistability in epigenome folding at sub-chromosomal scale. We show how experiments are fully consistent with multistable conformations where topologically associated domains of the same epigenomic state interact dynamically with each other. Our approach provides a general framework to improve our understanding of chromatin folding during cell cycle and differentiation and its relation to epigenetics.

In silico single-molecule manipulation of DNA with rigid body dynamics.

We develop a new powerful method to reproduce in silico single-molecule manipulation experiments. We demonstrate that flexible polymers such as DNA can be simulated using rigid body dynamics thanks to an original implementation of Langevin dynamics in an open source library called Open Dynamics Engine. We moreover implement a global thermostat which accelerates the simulation sampling by two orders of magnitude. We reproduce force-extension as well as rotation-extension curves of reference experimental studies. Finally, we extend the model to simulations where the control parameter is no longer the torsional strain but instead the torque, and predict the expected behavior for this case which is particularly challenging theoretically and experimentally.

Relevance and limitations of crowding, fractal, and polymer models to describe nuclear architecture.

Chromosome architecture plays an essential role for all nuclear functions, and its physical description has attracted considerable interest over the last few years among the biophysics community. These researches at the frontiers of physics and biology have been stimulated by the demand for quantitative analysis of molecular biology experiments, which provide comprehensive data on chromosome folding, or of live cell imaging experiments that enable researchers to visualize selected chromosome loci in living or fixed cells. In this review our goal is to survey several nonmutually exclusive models that have emerged to describe the folding of DNA in the nucleus, the dynamics of proteins in the nucleoplasm, or the movements of chromosome loci. We focus on three classes of models, namely molecular crowding, fractal, and polymer models, draw comparisons, and discuss their merits and limitations in the context of chromosome structure and dynamics, or nuclear protein navigation in the nucleoplasm. Finally, we identify future challenges in the roadmap to a unified model of the nuclear environment.

Prior exposure of endothelial cells to hydroxycarbamide alters the flow dynamics and adhesion of sickle red blood cells.

The hallmark of sickle cell disease (SCD) is vasoocclusive crisis (VOC). The sickle red blood cells (SS-RBCs) present enhanced adhesion to activated endothelial cells (ECs) as compared to normal RBCs (AA-RBCs) and believed to contribute to VOC. Hydroxycarbamide (HC), the sole drug thus far proven as efficacious at reducing VOC frequency, alters the expression of adhesion proteins both on RBCs and ECs. We investigated the functional effect of HC on the adhesive properties of ECs from the micro- or the macrocirculation (TrHBMEC, HPMEC, and HUVEC). Using a flow chamber, we analyzed RBC dynamics on the treated or untreated EC bed and firm adhesion in basal and inflammatory conditions. Most significant effects were obtained with ECs from the pulmonary microcirculation (HPMEC). HC treatment of ECs affects both transient interactions and firm adhesion of SS-RBCs to the EC bed. Indeed, first, HC-treatment of ECs decreases the number of firmly adherent SS-RBCs to the adhesion level of AA-RBCs in a VCAM-1 independent manner. Second, HC significantly increases the mean velocity of SS-RBCs and reduces the population of SS-RBCs in contact with the EC bed. These data provide additional evidence that modulation of SS-RBCs/ECs interactions by HC represents an important aspect of its mechanism of action.

High-throughput chromatin motion tracking in living yeast reveals the flexibility of the fiber throughout the genome.

Chromosome dynamics are recognized to be intimately linked to genomic transactions, yet the physical principles governing spatial fluctuations of chromatin are still a matter of debate. Using high-throughput single-particle tracking, we recorded the movements of nine fluorescently labeled chromosome loci located on chromosomes III, IV, XII, and XIV of Saccharomyces cerevisiae over an extended temporal range spanning more than four orders of magnitude (10(-2)-10(3) sec). Spatial fluctuations appear to be characterized by an anomalous diffusive behavior, which is homogeneous in the time domain, for all sites analyzed. We show that this response is consistent with the Rouse polymer model, and we confirm the relevance of the model with Brownian dynamics simulations and the analysis of the statistical properties of the trajectories. Moreover, the analysis of the amplitude of fluctuations by the Rouse model shows that yeast chromatin is highly flexible, its persistence length being qualitatively estimated to <30 nm. Finally, we show that the Rouse model is also relevant to analyze chromosome motion in mutant cells depleted of proteins that bind to or assemble chromatin, and suggest that it provides a consistent framework to study chromatin dynamics. We discuss the implications of our findings for yeast genome architecture and for target search mechanisms in the nucleus.

A predictive computational model of the dynamic 3D interphase yeast nucleus.

BACKGROUND: Despite the absence of internal membranes, the nucleus of eukaryotic cells is spatially organized, with chromosomes and individual loci occupying dynamic, but nonrandom, spatial positions relative to nuclear landmarks and to each other. These positional preferences correlate with gene expression and DNA repair, recombination, and replication. Yet the principles that govern nuclear organization remain poorly understood and detailed predictive models are lacking. RESULTS: We present a computational model of dynamic chromosome configurations in the interphase yeast nucleus that is based on first principles and is able to statistically predict the positioning of any locus in nuclear space. Despite its simplicity, the model agrees with extensive previous and new measurements on locus positioning and with genome-wide DNA contact frequencies. Notably, our model recapitulates the position and morphology of the nucleolus, the observed variations in locus positions, and variations in contact frequencies within and across chromosomes, as well as subchromosomal contact features. The model is also able to correctly predict nuclear reorganization accompanying a reduction in ribosomal DNA transcription, and sites of chromosomal rearrangements tend to occur where the model predicted high contact frequencies. CONCLUSIONS: Our results suggest that large-scale yeast nuclear architecture can be largely understood as a consequence of generic properties of crowded polymers rather than of specific DNA-binding factors and that configurations of chromosomes and DNA contacts are dictated mainly by genomic location and chromosome lengths. Our model provides a quantitative framework to understand and predict large-scale spatial genome organization and its interplay with functional processes.