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Mechanical regulation of chromatin and transcription

Abstract

Cells and tissues generate and are exposed to various mechanical forces that act across a range of scales, from tissues to cells to organelles. Forces provide crucial signals to inform cell behaviour during development and adult tissue homeostasis, and alterations in forces and in their downstream mechanotransduction pathways can influence disease progression. Recent advances have been made in our understanding of the mechanisms by which forces regulate chromatin organization and state, and of the mechanosensitive transcription factors that respond to the physical properties of the cell microenvironment to coordinate gene expression, cell states and behaviours. These insights highlight the relevance of mechanosensitive transcriptional regulation to physiology, disease and emerging therapies.

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Fig. 1: Cellular structures involved in mechanotransmission.
Fig. 2: Mechanotransduction of forces into biochemical information.
Fig. 3: General mechanisms by which mechanical forces can regulate gene expression.
Fig. 4: Mechanosensitive transcription factors in development and disease.
Fig. 5: Mechanosensitive transcription factors in vascular physiology and pathological remodelling.
Fig. 6: Mechanosensitive transcription factors in fibrosis and cancer.

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Acknowledgements

The authors are indebted to Y. Miroshnikova for reading the manuscript and providing thoughtful advice. They apologize to colleagues whose work they have inadvertently failed to cite. Work on nuclear mechanotransduction in the Dupont lab is supported by Worldwide Cancer Research grant no. 21-0156 and AIRC Foundation Investigator grant no. 21392, and in the Wickström lab by the Academy of Finland and Max Planck Society.

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Correspondence to Sirio Dupont or Sara A. Wickström.

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Glossary

Mechanical force

A force that is caused by contact with another object and that induces a change in state of rest or motion.

Shear

Occurs when a fluid applies a tangential force that pushes one part of the cell in one direction, and the rest of the cell is dragged in the opposite direction by adhesion to the extracellular matrix or to other cells.

Tensile stress

The action–reaction forces acting at the cell–extracellular matrix or cell–cell contact sites to stretch cells and to resist deformation. Tensile stress is the opposite of compression.

Hydrostatic pressure

A pressure exerted by a fluid onto a contact surface as a result of gravity.

Elasticity

The ability of a material to return to its original shape after a deformation-inducing force has been removed.

Viscosity

The ability of a fluid to resist gradual deformation. Most biological materials are considered viscoelastic, that is, they display properties of both elastic and viscous materials. Viscoelastic materials have a strain (deformation) rate that is dependent on time and they dissipate energy when a load is applied and removed whereas a purely elastic material does not.

Friction

A resistance that a surface encounters when it is moving over another surface, for example, in joints, tendons, eye or skin.

LINC complex

A multi-protein complex that crosses the nuclear envelope and provides a physical link between cytoplasmic and nuclear cytoskeletal structures.

Nuclear lamina

Structure between the inner nuclear membrane and peripheral chromatin, composed mainly of intermediate filament proteins, the lamins, and lamin-associated proteins.

Epidermal differentiation complex

(EDC). A gene complex of >50 genes that encode proteins involved in terminal differentiation and cornification of skin epidermal keratinocytes.

Mechanoadaptation

The process by which a cell subjected to mechanical forces reinforces its force-bearing structures.

Mediator complex

A multisubunit protein complex that bridges transcription factors and the basal RNA polymerase II transcriptional machinery.

Contact inhibition of growth

The process by which cell crowding inhibits cell proliferation through the establishment of cell–cell contacts and the reduction of cell size.

Cell competition

The active elimination of a viable but undesirable cell population by competitive interactions within a tissue.

Trophectoderm

The tissue of the pre-implantation mammalian embryo that will contribute to formation of the placenta.

Inner cell mass

The tissue of the pre-implantation mammalian embryo that will contribute to formation of the tissues of the fetus.

Granulosa

The somatic cells of the female gonad that surround oocytes and support their growth.

Branching morphogenesis

The developmental process by which a growing epithelium buds branches in the surrounding mesenchyme to form a tree-like structure.

Naive pluripotent state

Pluripotent stem cells equivalent to those found in the early inner cell mass, with largely unmethylated genome, and still able to differentiate into germ cells.

Regenerative medicine

The clinical use of stem cells to stimulate repair mechanisms and restore function in damaged body tissues or organs.

Laminar flow

When particles in a moving liquid follow linear paths without lateral mixing.

Sprouting angiogenesis

The growth of new capillary vessels out of pre-existing blood vessels.

Fibrotic response

Tissue remodelling characterized by the deposition of collagenous extracellular matrix, which can have a physiological function during wound healing (scarring) or a pathological function that can interfere with or totally inhibit the normal architecture and function of the underlying organ or tissue.

Cancer-associated fibroblasts

A population of cells, likely deriving from the fibroblast lineages, that are found in tumours and have an elongated morphology, are negative for epithelial, endothelial and leukocyte markers, and lack the mutations found in cancer cells.

Epithelial to mesenchymal transition

(EMT). The differentiation process by which cells lose epithelial identity and the ability to form stable cell–cell adhesions, and gain expression of mesenchymal markers associated with increased migratory ability.

Cholangiocellular transdifferentiation

The differentiation of hepatocytes into cells that express markers typically found in bile duct cells and in bipotent liver cell progenitors.

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Dupont, S., Wickström, S.A. Mechanical regulation of chromatin and transcription. Nat Rev Genet (2022). https://doi.org/10.1038/s41576-022-00493-6

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