Mechanosensitive genomic enhancers potentiate the cellular response to matrix stiffness

Epigenetic control of gene expression and cellular phenotype is influenced by changes in the local microenvironment, yet how mechanical cues precisely influence epigenetic state to regulate transcription remains largely unmapped. Here, we combine genome-wide epigenome profiling, epigenome editing, and phenotypic and single-cell RNA-seq CRISPR screening to identify a class of genomic enhancers that responds to the mechanical microenvironment. These “mechanoenhancers” can be preferentially activated on either soft or stiff extracellular matrix contexts and regulate transcription to influence critical cell functions including apoptosis, adhesion, proliferation, and migration. Epigenetic editing of mechanoenhancers reprograms the cellular response to the mechanical microenvironment and modulates the activation of disease-related genes in lung fibroblasts from healthy and fibrotic donors. Epigenetic editing of mechanoenhancers holds potential for precise targeting of mechanically-driven diseases.