Mechanoresponsive genomic enhancers potentiate the cellular response to matrix stiffness [hicar]
Epigenetic control of gene regulation and cell phenotype is influenced by changes in the mechanical microenvironment. Yet how mechanical forces precisely influence epigenetic state to regulate transcriptional responses remains largely unmapped. Here, we combine genome-wide epigenome profiling, epigenome editing, and phenotypic and single-cell RNA-seq screening to identify a sub-class of genomic enhancers that is responsive to the mechanical microenvironment. These enhancers regulate genes that act as key drivers for a variety of functional behaviors including apoptosis, mechanotransduction, proliferation, and migration. We find distinct patterns wherein subsets of mechano-enhancers can be preferentially active on either soft or stiff extracellular matrix (ECM) contexts. Epigenetic editing of these mechano-enhancers on rigid materials precisely tunes mechanically-induced gene expression to levels observed on softer materials, and broadly enables reprogramming of cellular response to the mechanical microenvironment. These mechanically-activated enhancers act as key signal transducers and may constitute a new class of targets that can be modulated to alter mechanically-driven disease states. Overall design: To investigate if mechanical stimuli altered 3-D chromatin interactions, we performed HiCAR (Hi-C on accessible regulatory DNA) on HFF cells cultured on either soft (1 kPa) or stiff (50 kPa) hydrogels