Modeling of Cell Nuclear Mechanics: Classes, Components, and Applications

Abstract

<jats:p>Cell nuclei are paramount for both cellular function and mechanical stability. These two roles of nuclei are intertwined as altered mechanical properties of nuclei are associated with altered cell behavior and disease. To further understand the mechanical properties of cell nuclei and guide future experiments, many investigators have turned to mechanical modeling. Here, we provide a comprehensive review of mechanical modeling of cell nuclei with an emphasis on the role of the nuclear lamina in hopes of spurring future growth of this field. The goal of this review is to provide an introduction to mechanical modeling techniques, highlight current applications to nuclear mechanics, and give insight into future directions of mechanical modeling. There are three main classes of mechanical models—schematic, continuum mechanics, and molecular dynamics—which provide unique advantages and limitations. Current experimental understanding of the roles of the cytoskeleton, the nuclear lamina, and the chromatin in nuclear mechanics provide the basis for how each component is subsequently treated in mechanical models. Modeling allows us to interpret assay-specific experimental results for key parameters and quantitatively predict emergent behaviors. This is specifically powerful when emergent phenomena, such as lamin-based strain stiffening, can be deduced from complimentary experimental techniques. Modeling differences in force application, geometry, or composition can additionally clarify seemingly conflicting experimental results. Using these approaches, mechanical models have informed our understanding of relevant biological processes such as migration, nuclear blebbing, nuclear rupture, and cell spreading and detachment. There remain many aspects of nuclear mechanics for which additional mechanical modeling could provide immediate insight. Although mechanical modeling of cell nuclei has been employed for over a decade, there are still relatively few models for any given biological phenomenon. This implies that an influx of research into this realm of the field has the potential to dramatically shape both future experiments and our current understanding of nuclear mechanics, function, and disease.</jats:p>

HP1α is a chromatin crosslinker that controls nuclear and mitotic chromosome mechanics

“…It is known that the mechanical contribution of chromatin to the short-extension force response of the nucleus depends on histone modification state ( Heo et al, 2016 ; Hobson and Stephens, 2020b ; Krause et al, 2019 ; Liu et al, 2018 ; Nava et al, 2020 ; Stephens et al, 2019b ; Stephens et al, 2018 ; Stephens et al, 2017 ). We considered the possibility that histone methylation contributes to mechanics through its impact on HP1α binding to chromatin ( Bannister et al, 2001 ; Erdel et al, 2020 ; Lachner et al, 2001 ; Nakayama et al, 2001 ).…”

“…This two-regime force response was recently verified by the AFM-SPIM force measurement technique ( Hobson et al, 2020a ). Chromatin-based nuclear mechanics are dictated by euchromatin and heterochromatin levels, particularly through post-translational modifications of histones by acetylation or methylation, respectively ( Heo et al, 2016 ; Hobson and Stephens, 2020b ; Krause et al, 2019 ; Liu et al, 2018 ; Nava et al, 2020 ; Stephens et al, 2019b ; Stephens et al, 2018 ; Stephens et al, 2017 ). These changes in chromatin-based nuclear mechanics can, independently of lamins, cause abnormal nuclear morphology, which is a hallmark of human disease ( Stephens et al, 2019a ).…”

“…Recent experimental and modeling studies suggest chromatin proteins, like HP1α, may contribute to mechanics by acting as physical linkers. Experimental data for nuclear mechanical response can only be reconciled with models which contain chromatin (an interior polymer), a lamina (a peripheral meshwork), and chromatin-chromatin and chromatin-lamina linkages ( Banigan et al, 2017 ; Hobson and Stephens, 2020b ; Stephens et al, 2017 ). Further studies have suggested that these linkages may govern nuclear shape stability ( Lionetti et al, 2020 ; Liu et al, 2021 ; Schreiner et al, 2015 ).…”

Modelling Nuclear Morphology and Shape Transformation: A Review

“…Here, we focus on continuum-level approaches while molecular dynamics simulations will not be discussed. Interested readers could refer to [ 58 ] for a review on that front. Specifically, different biophysical elements involved in regulating nuclear shape change will be discussed first before the introduction of three main types of continuum (i.e., energy minimization, boundary integral and finite element-based) models.…”

HP1α is a chromatin crosslinker that controls nuclear and mitotic chromosome mechanics

“…Recent experimental and modeling studies suggest chromatin proteins, like HP1α, may contribute to mechanics by acting as physical linkers. Experimental data for nuclear mechanical response can only be reconciled with models which contain chromatin (an interior polymer), lamina (a peripheral meshwork), and also chromatin-chromatin and chromatin-lamina linkages (Banigan et al, 2017; Hobson and Stephens, 2020; Stephens et al, 2017). Further studies have suggested that these linkages may govern nuclear shape stability (Lionetti et al, 2020; Liu et al, 2020; Schreiner et al, 2015).…”