Regulation of nuclear architecture, mechanics, and nucleocytoplasmic shuttling of epigenetic factors by cell geometric constraints

Abstract

Cells sense mechanical signals from their microenvironment and transduce them to the nucleus to regulate gene expression programs. To elucidate the physical mechanisms involved in this regulation, we developed an active 3D chemomechanical model to describe the three-way feedback between the adhesions, the cytoskeleton, and the nucleus. The model shows local tensile stresses generated at the interface of the cell and the extracellular matrix regulate the properties of the nucleus, including nuclear morphology, levels of lamin A,C, and histone deacetylation, as these tensile stresses 1) are transmitted to the nucleus through cytoskeletal physical links and 2) trigger an actomyosin-dependent shuttling of epigenetic factors. We then show how cell geometric constraints affect the local tensile stresses and subsequently the three-way feedback and induce cytoskeleton-mediated alterations in the properties of the nucleus such as nuclear lamina softening, chromatin stiffening, nuclear lamina invaginations, increase in nuclear height, and shrinkage of nuclear volume. We predict a phase diagram that describes how the disruption of cytoskeletal components impacts the feedback and subsequently induce contractility-dependent alterations in the properties of the nucleus. Our simulations show that these changes in contractility levels can be also used as predictors of nucleocytoplasmic shuttling of transcription factors and the level of chromatin condensation. The predictions are experimentally validated by studying the properties of nuclei of fibroblasts on micropatterned substrates with different shapes and areas.

Mechanical memory in cells emerges from mechanotransduction with transcriptional feedback and epigenetic plasticity

“…Mechanical strain and loading have also been shown to modulate chromatin remodeling enzymes like histone deacetylase (HDAC) and histone acetyltransferase (HAT) (51) and induce rapid chromatin condensation (51). Increasing contractility has been shown to regulate levels of HDACs, whereas available spreading area has been implicated in modulating HAT (54). Recently, it has been shown that stiff-primed stem cells continue to express an epigenetic modification factor HAT1 and suppress histone deacetylation enzymes (HDACs) even after they move to a soft matrix (33).…”

“…Recent experiments support this notion by showing upregulated HAT1 and downregulated HDACs when cells are primed sufficiently (33). Although it is known that nuclear shape, chromatin structure, and epigenetic state of the cell depend on matrix stiffness (25,28,29,54), it remains unclear how quickly these nuclear markers change when cells move to a new environment. Experiments could be also performed in which nuclei of differentially-primed cells are imaged through live-cell microscopy over time to verify that the nuclear structure and shape remain locked according to their past primed state.…”

Gap Junctions Amplify Spatial Variations in Cell Volume in Proliferating Solid Tumors

“…further understand how the two-way feedback between stress and signaling guides nuclear gene expression 47 , dynamic force generation 48 , and cancer invasion 13 . Importantly, in the current analysis we limit ourselves to the consideration of a single ion species and the associated channels and transporters, and therefore neglect the requirement of charge neutrality.…”

“…Clearly, our framework could be used to analyze such biological systems and provide mechanistic insight into their dependence on ion transport and differential cell swelling. Future advancements should also focus on detailing the interdependence between dynamic actomyosin contractility and cell osmolarity, building on our previous work to further understand how the two-way feedback between stress and signaling guides nuclear gene expression 47 , dynamic force generation 48 , and cancer invasion 13 . Importantly, in the current analysis we limit ourselves to the consideration of a single ion species and the associated channels and transporters, and therefore neglect the requirement of charge neutrality.…”

Image-based elastography of heterochromatin and euchromatin domains in the deforming cell nucleus

“…In the recent years, probing the mechanical properties of the heterochromatin and the euchromatin has gained significant interest because of the discovery of potential mechanisms that transduce mechanical forces into biological signals inside the cell nucleus -resulting into the emerging field of nuclear mechanobiology [9][10][11] . Mechanotransduction inside the nucleus is known to play critical roles in development, physiology, homeostasis and diseases 12,13 .…”