Department of Materials Science and Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104.
Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA 19104.
Proc Natl Acad Sci U S A. 2019 Jul 2;116(27):13200-13209. doi: 10.1073/pnas.1902035116. Epub 2019 Jun 17.
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.
细胞感知来自其微环境的机械信号，并将其转导至细胞核以调节基因表达程序。为了阐明这种调控涉及的物理机制，我们开发了一个主动的 3D 化学机械模型来描述细胞与细胞外基质之间的黏附、细胞骨架和细胞核之间的三向反馈。该模型表明，细胞与细胞外基质界面处产生的局部拉伸应力调节核的性质，包括核形态、核纤层 A、C 的水平和组蛋白去乙酰化，因为这些拉伸应力 1）通过细胞骨架物理连接传递到细胞核，2）触发肌动球蛋白依赖性的表观遗传因子穿梭。然后，我们展示了细胞的几何约束如何影响局部拉伸应力，进而影响三向反馈，并诱导核的性质发生细胞骨架介导的改变，如核纤层软化、染色质变硬、核纤层内陷、核高度增加和核体积缩小。我们预测了一个相图，描述了细胞骨架成分的破坏如何影响反馈，进而诱导核的收缩依赖性改变。我们的模拟表明，这些收缩水平的变化也可以作为转录因子核质穿梭和染色质浓缩水平的预测指标。通过研究具有不同形状和面积的微图案化基底上成纤维细胞的核性质，对预测进行了实验验证。
