Mechanomemory in protein diffusivity of chromatin and nucleoplasm after force cessation

Abstract

It is known that external mechanical forces can regulate structures and functions of living cells and tissues in physiology and diseases. However, after cessation of the force, how structures are altered in response to the dynamics of the chromatin and molecules in the nucleoplasm remains elusive. Here, using single-molecule imaging approaches, we show that exogenous local forces via integrins applied for 2 to 10 min decondensed the chromatin and increased chromatin and nucleoplasm protein mobility inside the nucleus, leading to elevated diffusivity of single protein molecules in the nucleoplasm, tens of minutes after the cessation of force. Diffusion experiments with fluorescence correlation spectroscopy in live single cells show that the mechanomemory in chromatin and nucleoplasm protein diffusivity was regulated by nuclear pore complexes. Protein molecular dynamics simulation recapitulated the experimental findings in live cells and showed that nucleoplasm protein diffusivity was regulated by the number of nuclear pore complexes. The mechanomemory in elevated protein diffusivity of the nucleoplasm after force cessation represents a physical process that reverses protein–protein condensation in phase separation via unjamming of the chromatin. Our findings of mechanomemory in chromatin and nucleoplasm protein diffusivity suggest that the effect of force on the nucleus remains tens of minutes after force cessation and thus is more far-reaching than previously anticipated.

Mechanical memory based on chromatin and metabolism remodeling promotes proliferation and smooth muscle differentiation in mesenchymal stem cells

“…Mechanical memory has been observed in various mechanical environments and cell lines, 5,8,37,38 yet the understanding of the key mechanisms that explain this biological phenomenon is limited. Our work demonstrates that MSCs exhibited mechanical memory in response to intermittent stretch, as evidenced by cell reorientation, alignment of F-actin, nuclear deformation, transcriptional activity, condensed chromatin, and active metabolism.…”

“…When MSCs were cultured on a stiff substrate, the microRNA miR‐21 served as a long‐term memory keeper of the osteogenic or fibrogenic program 6,7 . A recent study reported that mechanical memory also existed in the protein diffusivity of chromatin and nucleoplasm, which was regulated by nuclear pore complexes 8 …”

“…6,7 A recent study reported that mechanical memory also existed in the protein diffusivity of chromatin and nucleoplasm, which was regulated by nuclear pore complexes. 8 Dynamic stretch is associated with both physiological and pathological microenvironments for various cell types. It is widely used as a crucial pretreatment procedure in tissue engineering.…”

A nuclear basis for mechanointelligence in cells

“…1 ), but how stressing the nucleus causes permanent change to cells and gene expression is less clear. A key step in this sequence of events in the cell has now been revealed in a recent PNAS paper by Rashid et al., through the application of fluorescence correlation spectroscopy (FCS) to cells undergoing mechanical stimulus ( 1 ): Stressing of the cell’s cytoskeleton can lead to stressing of chromatin, leading to changes in mobility in the nucleus that last for tens of minutes. These new results are direct evidence of the existence of a time window of mechanosensation over which cells can lock in memory that drives phenotypic transitions ( 2 – 4 ).…”

“…But how does it all start, and what sets the timescales? A recent study in PNAS reveals that stretching of both chromatin and nuclear pores, induced by the direct cytoskeleton-mediated transmission of mechanical signals, plays an important role in the short-term after-effects of mechanical signals ( 1 ). In this study, application of local cyclic forces on the surface of cells for 10 min leads to chromatin decondensation, which in turn increases protein mobility inside the nucleus.…”