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Proc Natl Acad Sci U S A. 2019 Jul 2;116(27):13200-13209. doi: 10.1073/pnas.1902035116. Epub 2019 Jun 17.

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

Author information

1
Department of Materials Science and Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104.
2
Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, PA 19104.
3
Mechanobiology Institute, National University of Singapore, 117411, Singapore.
4
Department of Biological Sciences, National University of Singapore, 117411, Singapore.
5
FIRC Institute for Molecular Oncology (IFOM), 20139 Milan, Italy.
6
Department of Materials Science and Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104; vshenoy@seas.upenn.edu.

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.

KEYWORDS:

cell geometry; cytoskeletal mechanics; mechanotransduction; nuclear mechanics

PMID:
31209017
DOI:
10.1073/pnas.1902035116

Conflict of interest statement

The authors declare no conflict of interest.

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