Biology subjects

Paturej, J.

Publications and source records attributed to Paturej, J..

4 recordsLinked to original sources

bioRxiv2025

Peripheral heterochromatin tethering is required for chromatin-based nuclear mechanical response

The cell nucleus is a mechanically responsive structure that governs how external forces affect chromosomes. Chromatin, particularly transcriptionally inactive heterochromatin, resists nuclear deformations through its mechanical response. However, chromatin also exhibits liquid-like properties, casting ambiguity on the physical mechanisms of chromatin-based nuclear elasticity. To determine how heterochromatin strengthens nuclear mechanical response, we performed polymer physics simulations of a nucleus model validated by micromechanical measurements and chromosome conformation capture data. The attachment of peripheral heterochromatin to the lamina is required to transmit forces directly to the chromatin and elicit its elastic response. Thus, increases in heterochromatin levels increase nuclear rigidity by increasing the linkages between chromatin and the lamina. Crosslinks within heterochromatin, such as HP1 proteins, can also stiffen nuclei, but only if chromatin is peripherally tethered. In contrast, heterochromatin affinity interactions that may drive liquid-liquid phase separation do not contribute to nuclear rigidity. When the nucleus is stretched, gel-like peripheral heterochromatin can bear stresses and deform, while the more fluid-like interior euchromatin is less perturbed. Thus, heterochromatins internal structure and stiffness may regulate nuclear mechanics via peripheral attachment to the lamina, while also enabling nuclear mechanosensing of external forces and external measurement of the nucleus internal architecture.

biophysics↗

bioRxiv2024

Exploring Nuclear Lamina Structure and Lamin Dissociation in Progeria through Polymer Modeling

One of the key structural proteins in the eukaryotic cell nucleus is lamin. Lamins can assemble into a two-dimensional protein meshwork at the nuclear periphery, referred to as the nuclear lamina, which provides rigidity and shape to the nucleus. Mutations in lamin proteins that affect the structure of the nuclear lamina underlie laminopathic diseases, including Hutchinson-Gilford Progeria Syndrome (HGPS). Experiments have shown that, compared to healthy cells, lamin supramolecular structures (e.g., protofilaments) assemble into a thicker lamina structure in HGPS, where lamins form highly stable nematic microdomains at the nuclear periphery, reminiscent of liquid crystals. This significantly alters the morphological and mechanical properties of the nucleus. In this study, we investigate the aggregation of lamin fibrous structures and their dissociation kinetics from the nuclear periphery by modeling them as coarse-grained, rod-like polymer chains confined in a rigid spherical shell. Our model recapitulates the formation of multidirectional nematic domains at the nuclear surface and the reduced lamin dissociation observed in HGPS nuclei by adjusting lamin concentration, lamin-lamin (specifically head-tail), and lamin-shell association strengths. While nematic phase formation requires relatively strong lamin-shell affinity under any non-vanishing inter-lamin attraction, the thickness of this layer is primarily controlled by head-tail association strength in the model. Furthermore, the dissociation kinetics of lamin chains from the chain aggregates at the periphery (lamina) exhibits a concentration-dependent dissociation (facilitated dissociation) pattern governed by weak lamin-lamin interactions, reminiscent of healthy nuclei. Overall, our calculations demonstrate how an interplay between molecular interactions altered by mutations and lamin concentration can lead to an abnormal nuclear lamina in laminopathic diseases.

biophysics↗

bioRxiv2023

Polymer modelling suggests correlations between chromatin phase separation and nuclear shape fluctuations.

Abnormalities in the shapes of mammalian cell nuclei are hallmarks of a variety of diseases, including progeria, muscular dystrophy, and various cancers. Experiments have shown that there is a causal relationship between chromatin organization and nuclear morphology. Decreases in heterochromatin levels, perturbations to heterochromatin organization, and increases in euchromatin levels all lead to misshapen nuclei, which exhibit deformations, such as nuclear blebs and nuclear ruptures. However, the polymer physical mechanisms of how chromatin governs nuclear shape and integrity are poorly understood. To investigate how heterochromatin and euchromatin, which are thought to microphase separate in vivo, govern nuclear morphology, we implemented a composite coarse-grained polymer and elastic shell model. By varying chromatin volume fraction (density), heterochromatin levels and structure, and heterochromatin-lamina interactions, we show how the spatial organization of chromatin polymer phases within the nucleus could perturb nuclear shape in some scenarios. Increasing the volume fraction of chromatin in the cell nucleus stabilizes the nuclear lamina against large fluctuations. However, surprisingly, we find that increasing heterochromatin levels or heterochromatin-lamina interactions enhances nuclear shape fluctuations in our simulations by a "wetting"-like interaction. In contrast, shape fluctuations are largely insensitive to the internal structure of the heterochromatin, such as the presence or absence of chromatin-chromatin crosslinks. Therefore, our simulations suggest that heterochromatin accumulation at the nuclear periphery could perturb nuclear morphology in a nucleus or nuclear region that is sufficiently soft, while stabilization of the nucleus via heterochromatin likely occurs through mechanisms other than chromatin microphase organization.

biophysics↗

bioRxiv2023

Cyclic-polymer grafted colloids in spherical confinement: insights for interphase chromosome organization

Interphase chromosome structures are known to remain segregated in the micron-sized eukaryotic cell nucleus and occupy a certain fraction of nuclear volume, often without mixing. Using extensive coarse-grained simulations, we model such chromosome structures as colloidal particles whose surfaces are grafted by cyclic polymers. This model system is known as Rosetta. The cyclic polymers, with varying polymerization degrees, mimic the functionality of structural protein complexes, while the rigid core models the chromocenter sections of chromosomes. Our simulations show that the colloidal chromosome model provides a well-segregated particle distribution without specific attraction between the chain monomers. Notably, linear-polymer grafted particles also provide the same segregation scheme. However, unlike linear chains, cyclic chains result in less contact between the polymer layers of neighboring chromosome particles, demonstrating the effect of DNA breaks in altering genome-wide contacts. As the polymerization degree of the chains decreases while maintaining the total chromosomal length (the total polymer length per particle), particles form quasi-crystalline order, reminiscent of a glassy state. This order weakens for polymer chains with a characteristic size on the order of the confinement radius. Our simulations demonstrate that polymer systems can help decipher 3D chromosomal architectures along with fractal globular and loop-extrusion models.

biophysics↗