Biology subjects

Attar, A. G.

Publications and source records attributed to Attar, A. G..

3 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↗

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↗

bioRxiv2021

Facilitated Dissociation of Nucleoid Associated Proteins from DNA in the Bacterial Confinement

Transcription machinery depends on the temporal formation of protein-DNA complexes. Recent experiments demonstrated that lifetime of the complex can also affect transcription. In parallel, in vitro single-molecule studies showed that nucleoid-associated proteins (NAPs) leave the DNA rapidly as the bulk concentration of the protein increases via facilitated dissociation (FD). Never-theless, whether such concentration-dependent mechanism is functional in a bacterial cell, in which NAP levels and the 3D chromosomal structure are often coupled, is not clear a priori. Here, by using extensive coarse-grained molecular simulations, we model the unbinding of specific and nonspecific dimeric NAPs from a high-molecular-weight circular DNA molecule in a cylindrical structure mimicking the cellular confinement of a bacterial chromosome. Our simulations show that physiologically relevant peak protein levels (tens of micromolar) lead to highly compact chromosomal structures. This compaction results in rapid off rates (shorter DNA-residence times) but only for specifically DNA-binding NAPs such as the factor for inversion stimulation (Fis). Contrarily, for nonspecific NAPs, the off rates decrease as the protein levels increase, suggesting an inverse FD pattern. The simulations with restrained chromosome models reveal that this inverse response is due to DNA-segmental fluctuations, and that chromosomal compaction is in favor of faster protein dissociation. Overall, our results indicate that cellular-concentration level of a structural DNA-binding protein can be highly intermingled with its DNA-residence time.

biophysics↗