Experimental approaches have been applied to address questions in understanding three-dimensional chromatin organization and function. As datasets increase in size and complexity, it becomes a ...challenge to reach a mechanistic interpretation of experimental results. Polymer simulations and mechanistic modeling have been applied to explain experimental observations and their links to different aspects of genome function. Here we provide a guide for biologists, explaining different simulation approaches and the contexts in which they have been used.
Abstract
Current models for the folding of the human genome see a hierarchy stretching down from chromosome territories, through A/B compartments and topologically-associating domains (TADs), to ...contact domains stabilized by cohesin and CTCF. However, molecular mechanisms underlying this folding, and the way folding affects transcriptional activity, remain obscure. Here we review physical principles driving proteins bound to long polymers into clusters surrounded by loops, and present a parsimonious yet comprehensive model for the way the organization determines function. We argue that clusters of active RNA polymerases and their transcription factors are major architectural features; then, contact domains, TADs and compartments just reflect one or more loops and clusters. We suggest tethering a gene close to a cluster containing appropriate factors-a transcription factory-increases the firing frequency, and offer solutions to many current puzzles concerning the actions of enhancers, super-enhancers, boundaries and eQTLs (expression quantitative trait loci). As a result, the activity of any gene is directly influenced by the activity of other transcription units around it in 3D space, and this is supported by Brownian-dynamics simulations of transcription factors binding to cognate sites on long polymers.
We investigate the phase behavior and kinetics of a monodisperse mixture of active (i.e., self-propelled) and passive isometric Brownian particles through Brownian dynamics simulations and theory. As ...in a purely active system, motility of the active component triggers phase separation into a dense and a dilute phase; in the dense phase, we further find active-passive segregation, with "rafts" of passive particles in a "sea" of active particles. We find that phase separation from an initially disordered mixture can occur with as little as 15% of the particles being active. Finally, we show that a system prepared in a suitable fully segregated initial state reproducibly self-assembles an active "corona," which triggers crystallization of the passive core by initiating a compression wave. Our findings are relevant to the experimental pursuit of directed self-assembly using active particles.
Swimming bacteria create long-range velocity fields that stir a large volume of fluid and move around passive particles dispersed in the fluid. Recent experiments and simulations have shown that ...long-time mean-squared displacement of passive particles in a bath of swimming bacteria exhibits diffusive behaviour with an effective diffusion coefficient significantly larger than its thermal counterpart. A comprehensive theoretical prediction of this effective diffusion coefficient and the understanding of the enhancement mechanism remain a challenge. Here, we adapt the kinetic theory by Lin
et al.
,
J. Fluid Mech.
, 2011,
669
, 167 developed for 'squirmers' to the bacterial case to
quantitatively
predict enhanced diffusivity of tracer particles in dilute two- and three-dimensional suspensions of swimming bacteria. We demonstrate that the effective diffusion coefficient is a product of the bacterial number density, their swimming speed, a geometric factor characterising the velocity field created by a single bacterium, and a numerical factor. We show that the numerical factor is, in fact, a rather strong function of the system parameters, most notably the run length of the bacteria, and that these dependencies have to be taken into account to quantitatively predict the enhanced diffusivity. We perform molecular-dynamics-type simulations to confirm the conclusions of the kinetic theory. Our results are in good agreement with the values of enhanced diffusivity measured in recent two- and three-dimensional experiments.
Swimming bacteria create long-range velocity fields that stir a large volume of fluid and move around passive particles dispersed in the fluid.
Chromatin folded into 3D macromolecular structures is often analyzed by chromosome conformation capture (3C) and fluorescence in situ hybridization (FISH) techniques, but these frequently provide ...contradictory results. Chromatin can be modeled as a simple polymer composed of a connected chain of units. By embedding data for epigenetic marks (H3K27ac), chromatin accessibility (assay for transposase-accessible chromatin using sequencing ATAC-seq), and structural anchors (CCCTC-binding factor CTCF), we developed a highly predictive heteromorphic polymer (HiP-HoP) model, where the chromatin fiber varied along its length; combined with diffusing protein bridges and loop extrusion, this model predicted the 3D organization of genomic loci at a population and single-cell level. The model was validated at several gene loci, including the complex Pax6 gene, and was able to determine locus conformations across cell types with varying levels of transcriptional activity and explain different mechanisms of enhancer use. Minimal a priori knowledge of epigenetic marks is sufficient to recapitulate complex genomic loci in 3D and enable predictions of chromatin folding paths.
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•HiP-HoP: highly predictive heteromorphic polymer model to analyze chromatin structure•Polymer simulations use widely available epigenetic and protein binding data as input•Validate HiP-HoP model at complex loci using 3D FISH and Capture-C•Simulations uncover striking conformational variability in chromatin fiber folding
Buckle et al. develop a highly predictive heteromorphic polymer (HiP-HoP) model that uses epigenetic and protein binding data to predict 3D chromatin organizations, validated by FISH and Capture-C experiments. These simulations show striking conformation variability in fiber folding within a cell population and can explain different mechanisms of enhancer use.
Rotation and propulsion in 3D active chiral droplets Carenza, Livio Nicola; Gonnella, Giuseppe; Marenduzzo, Davide ...
Proceedings of the National Academy of Sciences - PNAS,
10/2019, Volume:
116, Issue:
44
Journal Article
Peer reviewed
Open access
Chirality is a recurrent theme in the study of biological systems, in which active processes are driven by the internal conversion of chemical energy into work. Bacterial flagella, actomyosin ...filaments, and microtubule bundles are active systems that are also intrinsically chiral. Despite some exploratory attempt to capture the relations between chirality and motility, many features of intrinsically chiral systems still need to be explored and explained. To address this gap in knowledge, here we study the effects of internal active forces and torques on a 3-dimensional (3D) droplet of cholesteric liquid crystal (CLC) embedded in an isotropic liquid. We consider tangential anchoring of the liquid crystal director at the droplet surface. Contrary to what happens in nematics, where moderate extensile activity leads to droplet rotation, cholesteric active droplets exhibit more complex and variegated behaviors. We find that extensile force dipole activity stabilizes complex defect configurations, in which orbiting dynamics couples to thermodynamic chirality to propel screw-like droplet motion. Instead, dipolar torque activity may either tighten or unwind the cholesteric helix and if tuned, can power rotations with an oscillatory angular velocity of 0 mean.
We explore a generic mechanism whereby a droplet of active matter acquires motility by the spontaneous breakdown of a discrete symmetry. The model we study offers a simple representation of a “cell ...extract” comprising, e.g., a droplet of actomyosin solution. (Such extracts are used experimentally to model the cytoskeleton). Actomyosin is an active gel whose polarity describes the mean sense of alignment of actin fibres. In the absence of polymerization and depolymerization processes (‘treadmilling’), the gel’s dynamics arises solely from the contractile motion of myosin motors; this should be unchanged when polarity is inverted. Our results suggest that motility can arise in the absence of treadmilling, by spontaneous symmetry breaking (SSB) of polarity inversion symmetry. Adapting our model to wall-bound cells in two dimensions, we find that as wall friction is reduced, treadmilling-induced motility falls but SSB-mediated motility rises. The latter might therefore be crucial in three dimensions where frictional forces are likely to be modest. At a supracellular level, the same generic mechanism can impart motility to aggregates of nonmotile but active bacteria; we show that SSB in this (extensile) case leads generically to rotational as well as translational motion.
Understanding the spatial organization of the genome in the cell nucleus is one of the current grand challenges in biophysics. Certain biochemical-or epigenetic-marks that are deposited along the ...genome are thought to play an important, yet poorly understood, role in determining genome organization and cell identity. The physical principles underlying the interplay between epigenetic dynamics and genome folding remain elusive. Here we propose and study a theory that assumes a coupling between epigenetic mark and genome densities, and which can be applied at the scale of the whole nucleus. We show that equilibrium models are not compatible with experiments and a qualitative agreement is recovered by accounting for nonequilibrium processes that can stabilize microphase separated epigenomic domains. We finally discuss the potential biophysical origin of these terms.
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