Speaker
Description
Background:
Cell adhesion can be guided through the mechanical signals provided by the biomaterials1,2. These signals are transmitted to the cytoskeleton, to the nuclei and finally to the chromatin3. The chromatin remodeling is highly dynamic and sensitive to these cues and imposes extensive effects on DNA-related metabolism, including transcription. Recently, chromatin has been identified as a mechanosensitive compartment that is shaped as much by external forces pressing down upon it, as internal forces pushing outwards from the chromatin: this dynamic process activate or silence genes. Chromatin therefore has a major role in the fate of the cell, in particular for the stem cell. Inversely, how chromatin communicates cues back to the nuclear membrane is poorly understand. Particularly, whether chromatin structure impacts by itself cell adhesion, more precisely the cell adhesion strength, is an underexplored topic.
Methods:
We have investigated if hyper-condensation of chromatin by ATP depletion (with sodium azide and 2-deoxyglucose, SA2D) or by inhibition of histone acetyltransferases (with anacardic acid, ANA) alters epithelial cell adhesion strength. This adhesion force is measured by fluidic force microscope (FluidFM), an atomic force microscope-driven micropipette4. Through this induced remodeling of chromatin, we investigated the organization of the cytoskeleton and focal adhesion.
Results:
Chromatin compaction within nuclei is induced by SA2D or by ANA. Our results demonstrate that this phenomenon is accompanied by a decrease of chromatin acetylation, an increase of histone H3K27 methylation and a decrease of the nuclear area. This leads to reorganization of the actin cytoskeleton showing small stress fibers localized around the nucleus while focal adhesion contacts decrease in size compare to untreated cells. By videomicroscopy, we show that after drugs remove from to the culture medium, cells morphologic are restored with nucleus decondensed. We observed by FluidFM that chromatin compaction by SA2D or ANA significantly decreases cell adhesion strength compared to untreated cells.
Conclusions:
These results show for the first time that structure of the chromatin physically impact cell adhesion strength. Moreover, this chromatin remodeling is correlated with a global deacetylation of the nucleus and impact the dynamic of the cytoskeleton and the focal adhesion contacts.
A new open question is to determine how cell adhesion strength is mechanically impacted by chromatin structure, especially during stem cell differentiation and thus could provide essential data in epigenetic cell reprogramming for stem cell tissue engineering. Another attractive question will be to determine how a cell rapidly coordinates external forces with internal genomic forces to accomplish mechanosensitive biological processes.
References
1. Rabineau, M. et al. Cell guidance into quiescent state through chromatin remodeling induced by elastic modulus of substrate. Biomaterials 37, 144–155 (2015).
2. Rabineau, M. et al. Chromatin de-condensation by switching substrate elasticity. Sci. Rep. 8, 12655 (2018).
3. Argentati, C. et al. Insight into Mechanobiology: How Stem Cells Feel Mechanical Forces and Orchestrate Biological Functions. Int. J. Mol. Sci. 20, 5337 (2019).
4. Guillaume-Gentil, O. et al. Force-controlled manipulation of single cells: from AFM to FluidFM. Trends Biotechnol. 32, 381–388 (2014).
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