Modeling Nuclear Blebs in a Nucleoskeleton of Independent Filament Networks

Abstract

Correlations between altered nuclear shape and disease are empirically observed, but the causes of nuclear dysmorphisms are poorly understood. The nucleoskeleton, which provides the majority of the mechanical stability of the nucleus, is composed primarily of intermediate filaments of lamin proteins. The nucleoskeleton forms a mostly-planar network between the inner nuclear membrane and chromatin. It is unclear if blebs and larger scale changes in nuclear morphology are consequences of reorganization of the nucleoskeleton alone or of other cellular processes. To test this, we computationally recapitulate the lamina network using a mechanical network model created as a network of Hookean springs. A- and B-type lamin filaments were distributed over a spherical surface into distinct networks linked to one another by lamin-associated proteins. Iterative force-based adjustment of the network structure, together with a stochastically modified Bell model of bond breakage and formation, simulates nucleoskeleton reorganization with blebs. The rate of bleb retraction into the nucleus depends on both initial size of the bleb and number of networks being deformed. Our results show that induced blebs are more stable when only one filament component is deformed or when the networks have no interconnections. Also, the kinetics of retraction is influenced by the composition of the bleb. These results match with our experiments and others.

Cytoskeletal tension induces the polarized architecture of the nucleus

“…This ultimately results in the apical accumulation of nuclear lamin A/C rather than the random localization in the periphery and interior of the nucleus. Consequently, when the actin cap disappears, the resulting reduced level of nuclear pressure applied to the nuclear lamina drives apically polarized dense lamin A/C network back to a less compact state (i.e., less condensed condition similar to swollen gels), which exerts higher deformability of lamin networks to be remodeled[56, 57]. …”

Mechanics and buckling of biopolymeric shells and cell nuclei

“…These deformations of the lamina are hypothesized to arise via defective force response (28)(29)(30)(31)(32). Indeed, two models have investigated this hypothesis, finding that phase separation between different types of lamins (33) or disruption of the connectivity of the lamina (34) can result in bleb-like deformations of shells. However, recent experiments demonstrate that chromatin, the packaged genome inside the nucleus, also controls cell nuclear mechanics and morphology, and in some cases, is the dominant component (19,(35)(36)(37).…”

Chromatin histone modifications and rigidity affect nuclear morphology independent of lamins

“…These blebs have been characterized as lacking lamin B1, exhibiting a distended lamin A network, and containing decompact euchromatin (Butin-Israeli et al, 2012). Currently, the prevailing hypothesis for the mechanism of bleb formation is that alterations to lamins destabilize the lamina, either passively (Funkhouser et al, 2013) or through response to mechanical perturbations (Wren et al, 2012;Cao et al, 2016). In the former model, phase separation of lamins A and B lead to aberrant structure, whereas in the latter, the less mechanically robust nuclear envelope is distended and/or ruptured by external forces.…”