Intra-Nuclear Tensile Strain Mediates Reorganization of Epigenetically Marked Chromatin During Cardiac Development and Disease

Environmental mechanical cues are critical to guide cell fate. Forces transmit to the nucleus through the Linker of Nucleo- and Cytoskeleton (LINC) complex and are thought to influence the organization of chromatin that is related to cell differentiation; however, the underlying mechanisms are unclear. Here, we investigated chromatin reorganization during murine cardiac development and found that cardiomyocytes establish a distinct architecture characterized by relocation of H3K9me3-modified chromatin from the nuclear interior to the periphery and co-localization to myofibrils. This effect was abrogated in stiff environments that inhibited cardiomyocyte contractility, or after LINC complex disruption, and resulted in the relocation of H3K27me3-modified chromatin instead. By generating high-resolution intra-nuclear strain maps during cardiomyocyte contraction, we discovered that the reorganization of H3K9me3-marked chromatin is influenced by tensile, but not compressive, nuclear strains. Our findings highlight a new role for nuclear mechanosensation in guiding cell fate through chromatin reorganization in response to environmental cues.