Regulation of genome organization and gene expression by nuclear mechanotransduction

Key Points

  • Cellular mechanical states modulate cytoskeleton–nucleus links and trigger the translocation of regulatory molecules to the nucleus.

  • The remodelling of cytoskeleton–nucleus links results in distinct morphological as well as mechanical and dynamic properties of the cell nucleus.

  • The cell type-specific organization of chromosomes and their intermingling is modulated by the mechanical state of a cell.

  • The recruitment of transcription factors to their target genes is facilitated by the nuclear mechanical state through the establishment of particular chromosome neighbourhoods and functional gene clusters.

  • Such cell type-specific chromosome neighbourhoods and gene clusters are established during cell differentiation.

  • The spatial organization of chromosomes and their intermingling are crucial for mechanoregulation of gene expression, and alterations thereof can result in the onset of various diseases.

Abstract

It is well established that cells sense chemical signals from their local microenvironment and transduce them to the nucleus to regulate gene expression programmes. Although a number of experiments have shown that mechanical cues can also modulate gene expression, the underlying mechanisms are far from clear. Nevertheless, we are now beginning to understand how mechanical cues are transduced to the nucleus and how they influence nuclear mechanics, genome organization and transcription. In particular, recent progress in super-resolution imaging, in genome-wide application of RNA sequencing, chromatin immunoprecipitation and chromosome conformation capture and in theoretical modelling of 3D genome organization enables the exploration of the relationship between cell mechanics, 3D chromatin configurations and transcription, thereby shedding new light on how mechanical forces regulate gene expression.

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Figure 1: Nuclear mechanotransduction.
Figure 2: Crosstalk between the serum response pathway, the NF-κB pathway and global chromatin remodelling.
Figure 3: The modulation of chromosome intermingling and gene neighbourhoods is induced by cell mechanical constraints.
Figure 4: The modularity in chromosome organization and gene expression depends on nuclear mechanical state.

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Acknowledgements

C.U. was partially supported by the US Defense Advanced Research Projects Agency (DARPA) (W911NF-16-1-0551), the National Science Foundation (NSF) (1651995) and the US Office of Naval Research (N00014-17-1-2147). G.V.S. was funded by the Mechanobiology Institute, Singapore, the MOE-Tier 3 grant, Singapore, and the Italian Foundation for Cancer Research (FIRC) Institute of Molecular Oncology (IFOM), Milan, Italy. The authors thank members of the Uhler and Shivashankar laboratories for useful discussions.

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Both authors contributed to researching data for the article, discussion of the content and writing, reviewing and editing of the manuscript.

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Correspondence to G. V. Shivashankar.

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PowerPoint slides

Glossary

Transdifferentiation

The process in which a somatic cell is transformed into another type of somatic cell.

Integrins

Cell surface transmembrane receptors involved in mechanosensing.

Focal adhesion complexes

Cell membrane protein complexes that connect the actin cytoskeleton with the extracellular matrix.

Cadherin

A transmembrane receptor that bridges cell–cell junctions.

Actomyosin

Protein complexes comprising actin and myosin; they form contractile units.

Junction proteins

Proteins that bridge the cytoskeleton of two neighbouring cells through the cell–cell junction.

Magnetic twisting cytometry

A technique for applying precise forces to single cells.

Visco-elastic coupling

The propensity of materials to exhibit viscous and elastic responses when deformed.

Inverted formins

Actin-nucleating proteins located on the endoplasmic reticulum and other cellular organelles.

G-actin

The globular form of monomeric actin.

Entropic pressure

Forces generated by the intrinsic thermodynamic tendency to increase entropy.

Progeria

A genetic disorder of premature ageing.

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Uhler, C., Shivashankar, G. Regulation of genome organization and gene expression by nuclear mechanotransduction. Nat Rev Mol Cell Biol 18, 717–727 (2017). https://doi.org/10.1038/nrm.2017.101

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