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Register a new userPolymer Modelling Predicts Chromosome Reorganisation in Senescence
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Lamina-associated domains (LADs) cover a large part of the human genome and are thought to play a major role in shaping the nuclear architectural landscape. Here, we perform polymer simulations, microscopy and mass spectrometry to dissect the roles played by heterochromatin- and lamina-mediated interactions in nuclear organisation. Our model explains the conventional organisation of heterochromatin and euchromatin in growing cells and the pathological organisation found in oncogene-induced senescence and progeria. We show that the experimentally observed changes in the locality of contacts in senescent and progeroid cells can be explained as arising due to phase transitions in the system. Within our simulations LADs are highly stochastic, as in experiments. Our model suggests that, once established, the senescent phenotype should be metastable even if lamina-mediated interactions were reinstated. Overall, our simulations uncover a generic physical mechanism that can regulate heterochromatin segregation and LAD formation in a wide range of mammalian nuclei.
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Cells possess non-membrane-bound bodies, many of which are now understood as phase-separated condensates. One class of such condensates is composed of two polymer species, where each consists of repeated binding sites that interact in a one-to-one fashion with the binding sites of the other polymer. Previous biologically-motivated modeling of such a two-component system surprisingly revealed that phase separation is suppressed for certain combinations of numbers of binding sites. This phenomenon, dubbed the magic-number effect, occurs if the two polymers can form fully-bonded small oligomers by virtue of the number of binding sites in one polymer being an integer multiple of the number of binding sites of the other. Here we use lattice-model simulations and analytical calculations to show that this magic-number effect can be greatly enhanced if one of the polymer species has a rigid shape that allows for multiple distinct bonding conformations. Moreover, if one species is rigid, the effect is robust over a much greater range of relative concentrations of the two species. Our findings advance our understanding of the fundamental physics of two-component polymer-based phase-separation and suggest implications for biological and synthetic systems.
We propose a model for the formation of chromatin loops based on the diffusive sliding of a DNA-bound factor which can dimerise to form a molecular slip-link. Our slip-links mimic the behaviour of cohesin-like molecules, which, along with the CTCF protein, stabilize loops which organize the genome. By combining 3D Brownian dynamics simulations and 1D exactly solvable non-equilibrium models, we show that diffusive sliding is sufficient to account for the strong bias in favour of convergent CTCF-mediated chromosome loops observed experimentally. Importantly, our model does not require any underlying, and energetically costly, motor activity of cohesin. We also find that the diffusive motion of multiple slip-links along chromatin may be rectified by an intriguing ratchet effect that arises if slip-links bind to the chromatin at a preferred loading site. This emergent collective behaviour is driven by a 1D osmotic pressure which is set up near the loading point, and favours the extrusion of loops which are much larger than the ones formed by single slip-links.
In eukaryotic cells, KDEL receptors (KDELRs) facilitate the retrieval of endoplasmic reticulum (ER) luminal proteins from the Golgi compartment back to the ER. Apart from the well-documented retention function, recent findings reveal that the cellular KDELRs have more complex roles, e.g. in cell signalling, protein secretion, cell adhesion and tumorigenesis. Furthermore, several studies suggest that a sub-population of KDELRs is located at the cell surface, where they could form and internalize KDELR/cargo clusters after K/HDEL-ligand binding. However, so far it has been unclear whether there are cell-type- or species-specific differences in KDELR clustering. By comparing ligand-induced KDELR clustering in different mouse and human cell lines via live cell imaging, we show that macrophage cell lines from both species do not develop any clusters. Using RT-qPCR experiments and numerical analysis, we address the role of KDELR expression as well as endocytosis and exocytosis rates on the receptor clustering at the plasma membrane and discuss how the efficiency of directed transport to preferred docking sites on the membrane influences the exponent of the power-law distribution of the cluster size.
A biomimetic model of cell-cell communication was developed to probe the passive molecular transport across ion channels inserted in synthetic lipid bilayers formed between contacting droplets arranged in a linear array. Diffusion of a fluorescent probe across the array was measured for different pore concentrations. The diffusion characteristic time scale is found to vary non-linearly with the pore concentration. Our measurements are successfully modeled by a continuous time random walk description, whose waiting time is the first exit time from a droplet through a cluster of pores. The size of the cluster of pores is found to increase with their concentration. Our results provide a direct link between the mesoscopic permeation properties and the microscopic characteristics of the pores such as their number, size and spatial arrangement.
We present a generalized Landau-Brazovskii theory for the solidification of chiral molecules on a spherical surface. With increasing sphere radius one encounters first intervals where robust achiral density modulations appear with icosahedral symmetry via first-order transitions. Next, one en- counters intervals where fragile but stable icosahedral structures still can be constructed but only by superposition of multiple irreducible representations. Chiral icoshedral structures appear via continuous or very weakly first-order transitions. Outside these parameter intervals, icosahedral symmetry is broken along a three-fold axis or a five-fold axis. The predictions of the theory are compared with recent numerical simulations.
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