Substrate stiffness dominants cell gene expression via regulation of HDAC3 subcellular localization

Adhesive interface stiffness is capable of modulating cellular behavior and gene expression, yet the underlying mechanobiological mechanisms remain unclear. In this study, we investigated the effects of interface stiffness on gene expression pathways by hydrogels with divergent stiffness. Our results reveal that adhesive interface stiffness affects cytoplasmic mechanotranduction as well as nuclear mechanics, and ultimately regulating the subcellular localization of HDAC3. Further investigation unfolds that HDAC3 directly affects global acetylation levels within nucleus. And HDAC3-induced acetylation changes are regulated by myosin contraction, thereby portraying downstream gene expression. Additionally, our study indicates that the interface stiffness-mediated regulation of HDAC3 nuclear-cytoplasmic redistribution is dependent on CRM1, and inhibition of CRM1 impedes the nuclear export of HDAC3. In summary, our work provides an overview of how the subcellular localization of HDAC3 can be manipulated through the regulation of cell adhesion interface stiffness, thereby altering upstream RNA polymerase II activity and gene expression.