Nikhil Jaina,b,c, K. Venkatesan Iyera , Abhishek Kumara, and G. V. Shivashankara,b,c,1
Published online before print June 24, 2013, doi:10.1073/pnas.1300801110. PNAS June 24, 2013
Physical forces in the form of substrate rigidity or geometrical constraints have been shown to alter gene expression proﬁle and differentiation programs. However, the underlying mechanism of gene regulation by these mechanical cues is largely unknown.
In this work, we use micropatterned substrates to alter cellular geometry (shape, aspect ratio, and size) and study the nuclear mechanotransduction to regulate gene expression.
Genome-wide transcriptome analysis revealed cell geometry-dependent alterations in actin-related gene expression. Increase in cell size reinforced expression of matrix-related genes, whereas reduced cell-substrate contact resulted in up-regulation of genes involved in cellular homeostasis.
We also show that large-scale changes in geneexpression proﬁle mapped onto differential modulation of nuclear morphology, actomyosin contractility and histone acetylation. Interestingly, cytoplasmic-to-nuclear redistribution of histone deacetylase 3 modulated histone acetylation in an actomyosin-dependent manner.
In addition, we show that geometric constraints altered the nuclear fraction of myocardin-related transcription factor. These fractions exhibited hindered diffusion time scale within the nucleus, correlated with enhanced serum-response element promoter activity.
Furthermore, nuclear accumulation of myocardin-related transcription factor also modulated NF-κB activity. Taken together, our work provides modularity in switching gene expression patterns by cell geometric constraints via actomyosin contractility.
Learn more about GV Shivashankar‘s research.
aMechanobiology Institute, National University of Singapore, Singapore 117411
bDepartment of Biological Sciences, National University of Singapore,Singapore 117543
cCentre for Bio-Imaging Sciences, Department of Biological Sciences, National University of Singapore, Singapore 117543