Increased matrix stiffness promotes fibrogenesis of hepatic stellate cells through AP-1-induced chromatin priming

Matrix stiffness can have significant effects on cell behavior, regulating processes such as proliferation, differentiation, migration, and extracellular matrix production; however, less is known regarding the epigenomic and transcriptional regulation underling the effect of matrix stiffness on cell phenotypic shifts. In the present study, we utilized an in vitro system to assess the phenotypic shifts of hepatic stellate cells (HSCs) following changes in matrix stiffness, in addition to integrating multi-omics with imaging and biochemical assays to investigate the mechanism underlying the effect of mechanical stimuli on fibrosis. We show that cells cultured on a stiff matrix display more accessible chromatin sites, which consist of primed chromatin regions that become more accessible prior to the upregulation of nearby genes. These regions are enriched in fibrosis-associated genes that function in cytoskeletal organization and response to mechanical stimuli. Mechanistically, we demonstrate that activation of the AP-1 transcription factor family is responsible for chromatin priming, among which activated p-JUN is critical for the promotion of fibrogenic phenotypic shifts. The identified chromatin accessibility-dependent effect of matrix stiffness on cellular phenotypic shifts may be responsible for various fibrotic diseases and provide insight into intervening approaches.