Geometric Constraints on Cells Induce Cytoplasmic to Nuclear Redistribution of Transcription Co-Factors to Regulate Gene Expression

Abstract

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. We show that geometric constraints result in differential modulation of nuclear morphology, acto-myosin contractility, histone acetylation and the activity of transcription co-factor, MRTF-A. In addition, genome-wide transcriptome analysis revealed cell geometry dependent alterations in chromosomal activity and actin dependent gene expression. Promoter analysis of these differentially regulated genes showed that serum response factor (SRF) was an essential regulatory factor sensitive to geometric cues. Further, we show that geometric constraints resulted in nuclear translocation of MRTF-A and enhanced serum response element (SRE) promoter activity. Interestingly, nuclear accumulation of MRTF-A by geometric constraints also modulated NF-κB activity. Taken together, our work provides mechanistic insights underlying the regulation of gene expression by cellular geometry.