PerspectiveCell Biology

Strength Under Tension

See allHide authors and affiliations

Science  30 Aug 2013:
Vol. 341, Issue 6149, pp. 965-966
DOI: 10.1126/science.1243643

Mechanics control gene expression to modulate tissue-specific differentiation, but the molecular mechanisms that underlie these effects remain unclear. On page 1240104 of this issue, Swift et al. (1) link tissue specificity and extracellular matrix stiffness to the relative abundance of the nuclear envelope protein lamin A. The findings support the idea that mechanical links exist between the nucleus and the extracellular microenvironment that direct cell fate, and imply that force mediates these effects by altering the biophysical properties of the nucleus.

Mechano-response.

Tension from the extracellular matrix affects cytoskeletal tension on the nucleus. This affects the turnover of lamin A in the nuclear envelope, expression of LMNA, and stiffness of the nucleus.

CREDIT: V. ALTOUNIAN/SCIENCE

Mechanical forces are generated at the cell and tissue level through cell-cell and cell–extracellular matrix interactions. Cells sense, translate, and transmit mechanical cues from their periphery to the nucleus and induce changes in gene expression (2). This is accomplished in part by receptor-mediated tuning of biochemical and transcriptional circuits. Alternatively, mechanical cues can transmit forces through physical links between the nuclear membrane and the extracellular space. These connections distort the nuclear envelope and evoke transcriptional changes by locally altering the spatial accessibility of chromatin to transcriptional regulators (3, 4). Such changes occur rapidly and proportionately to the extent of the deformation (5), but histone deacetylase activity eventually increases after prolonged stress. This modification of histones condenses chromatin, thereby modifying transcription. Swift et al. show that the force environment can change transcription of the gene LMNA and stability of the encoded protein, lamin A/C, to alter nuclear rheology. This indicates that mechanically driven cell differentiation involves interdependent changes in nuclear composition and transcriptional state.

Cells not only regulate their cytoskeletal organization, cell shape, polarity, and molecular state but also modify the extracellular matrix composition and topology to achieve tensional homeostasis. In this manner, cells can both sense and dictate the physical properties of their microenvironment while preserving the structural continuity within the surrounding tissue. Consequently, tissues acquire stiffness optima as an emergent property of the physical and biochemical interactions between their constituent cells. This tensional equilibrium confers macroscopic compliance properties that are critical for processes such as stem cell differentiation, embryonic development, and tissue homeostasis.

The specific mechanisms by which individual cells physically remodel themselves to functionally drive macroscopic changes in tissue compliance are not well understood, however. In addition to responding dynamically to immediate physical cues, cells must integrate mechanical signals to alter their long-term molecular state and cellular phenotype. Accordingly, such mechanisms must operate on long time scales to promote phenotypic stabilization, likely by directing transcriptional and epigenetic changes.

Swift et al. show that the relative abundance of lamin A is a key component of mechanoreciprocal responses and a major determinant of cell and tissue stiffness (see the figure). The authors observed that increased cell tension reduces the turnover of lamin A in the nuclear lamina. This causes accumulation of the mechanosensitive Yes-associated protein (YAP), a master transcriptional regulator. An increase in lamin A also triggers the serum response factor (SRF) signaling pathway, whose gene targets control the actin cytoskeleton. The accumulation of lamin A also drives translocation of the retinoic acid receptor into the nucleus to stimulate transcription of LMNA and the production of more lamin A. The findings suggest a mechanism that could explain the strong correlation between relative abundance of lamin A in diverse cell types with macroscopic tissue stiffness. Interestingly, as the relative abundance of lamin A increases, the viscosity of the nucleus also increases. It is possible that in addition to activating mechanosignaling pathways, an increase in lamin A may play a role in physically stiffening the nucleus as part of the cellular response to increased tension.

The model presented by Swift et al. proposes how cells that are otherwise acutely sensitive to mechanical signals can structurally acclimate to tissue environments that are pervasively subject to a sizable mechanical load. In such circumstances, lamin A could physically reinforce the nuclear envelope, which would stabilize interactions between chromatin and the nuclear lamina and inure the cell to subsequent nuclear distortions that might otherwise occur in a high-tension tissue environment. Indeed, such an observation could explain why many tumors, which are typically stiffer than the surrounding tissue and are characterized by increased interstitial pressure, also often have greater amounts of lamin A compared to normal cells (6, 7). Moreover, the model hints at a deeper interplay between mechanosensitive signaling pathways, which are apparently affected by both external stress and elevated lamin A abundance, and transcriptional changes that are induced by direct tension on the nucleus from cytoskeletal contacts, which are likely to be modified in cells with lamin A–rich nuclear envelopes. Alternatively, increased tissue-level stiffness might compensate for lamin A–induced changes in nuclear compliance, such that the cytoskeleton simply transmits a greater mechanical load to enable cytoskeletal contact points on the nucleus to remain mechanically sensitive.

The provocative feed-forward mechanism governing lamin A concentration in the model of Swift et al. is critically dependent on retinoic acid receptor activity and provides another potential layer of mechanosensitive regulation. For instance, in the absence of ligand, the retinoic acid receptor will heterodimerize with one of the nuclear receptor co-repressor repressor proteins which, together with their associated histone deacetylases, inhibits transcription from specific promoters to maintain heterochromatin. Given the importance of the nuclear lamina in stabilizing heterochromatin, the data presented by Swift et al. implicate epigenetic silencing of lamina-associated chromatin as a key component of tension-mediated transcriptional regulation.

Additional studies are required to explicitly link mechano-reciprocal nuclear stiffening to gene-regulatory mechanisms. Elucidating the phenomena that collectively define cellular mechanosensation will also require studies to more completely unify the functionality of direct and indirect force-mediated transcriptional mechanisms. For cells, it seems that tension can become a source of considerable strength.

References

View Abstract

Stay Connected to Science

Navigate This Article