Mechanical Regulation of Histone H3 Modifications Via Matrix Rigidity during TGF?1-Induced Epithelial-Mesenchymal Transition

Epithelial-Mesenchymal Transition (EMT) is a biological process that is important in development and has been implicated in carcinogenesis and fibrosis. During EMT, cells lose apical-basal polarity, experience gene expression changes, and gain enhanced motility. The extracellular matrix (ECM) surrounding cells plays a major role in regulating cellular functions and studies have shown that increased ECM rigidity promotes gene expression changes associated with EMT. In addition, evidence supports epigenetic remodeling during EMT, however, there is limited knowledge available on how the mechanical properties of the ECM control chromatin and nuclear architecture along with histone modifications in the context of EMT. Here, we synthesized hydrogels with stiffnesses spanning that of normal and diseased mammary tissue and examined the effect of matrix rigidity on mammary epithelial cells during transforming growth factor (TGF) β1-induced EMT. Using experimental assays such as immunofluorescence staining and western blotting, we find that matrix rigidity modulates bulk levels of histone H3 modifications during TGFβ1-induced EMT. These modifications are associated with transcriptional activation and silencing. Furthermore, cell contractility inhibitors modulate the levels of histone markers in response to increasing matrix rigidity and TGFβ1 treatment. These findings suggest that matrix rigidity contributes to epigenetic remodeling and subsequent gene transcription in the context of the EMT process. This, in turn, will help to identify approaches to control EMT processes in pathological conditions such as fibrosis and cancer metastasis.